Open Access

Roles of DNA damage repair and precise targeted therapy in renal cancer (Review)

  • Authors:
    • Yongchang Lai
    • Zhibiao Li
    • Zechao Lu
    • Hanxiong Zheng
    • Chiheng Chen
    • Can Liu
    • Yafei Yang
    • Fucai Tang
    • Zhaohui He
  • View Affiliations

  • Published online on: October 19, 2022
  • Article Number: 213
  • Copyright: © Lai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


The primary subtypes of renal cell carcinoma (RCC) include clear cell, papillary and chromophobe RCC. RCC occurs often due to loss of von Hippel‑Lindau (VHL) and accumulation of lipids and glycogen, and RCC cells may exhibit sensitivity to the disruption of normal metabolism or homologous recombination gene defect. Although the application of molecular‑targeted drugs (tyrosine kinase inhibitors) and immune checkpoint inhibitors has been recommended for the treatment of advanced RCC, more targets of DNA damage repair (DDR) signaling pathway involved in the synthetic lethal effect have been investigated. However, although achievements has been made in the exploration of the roles of DDR genes on RCC progression, their association has not been systematically summarized. Poly (ADP‑ribose) polymerase (PARP) 1 inhibitors are used in tumors with BRCA1/2 DNA repair‑associated mutations. PARP family enzymes perform post‑translational modification functions and participate in DDR and cell death. Inhibitors of PARP, ataxia telangiectasia mutant gene and polymerase θ serve key roles in the treatment of specific RCC subtypes. PARP1 may serve as an important biological marker to predict the therapeutic effect of immune checkpoint inhibitors and evaluate the prognosis of patients with ccRCC with polybromo 1 mutation. Therefore, the roles of DDR pathway on RCC progression or treatment may hold promises for the treatment of certain specific types of RCC.


Physical external factors (ultraviolet, ionizing radiation), chemical drugs or poisons [benzo(a)pyrene, alkylating agents, platinum compounds, psoralens], as well as endogenous byproducts (metabolites, free radicals) result in numerous forms of DNA damage in cells (1). The primary pathways for DNA damage repair (DDR) include mismatch repair, nucleotide excision repair (NER) and base excision repair (BER) for single-strand break (SSB) and double-strand break (DSB) repair mechanisms (2).

Homologous recombination (HR), classical non-homologous end joining (NHEJ), alternative end joining and single strand annealing repair are key repair pathways of DSBs (3). The HR-based repair pathway, known as gene transformation pathway, is generally considered to be the sole error-free pathway that maintain DNA integrity and initial DNA sequence. The poly (ADP-ribose) polymerase (PARP) family consists of 17 abundant nuclear enzymes that are present in the majority of eukaryotic cells and promote formation of ADP-ribose polymer (PAR) (4). DNA damage recruits and activates PARP-1 and PARP-2, leading to ADP-ribosylation at multiple sites. PARP-1 mediates several processes involved in DNA metabolism, such as single-strand damage repair, NER, DSB repair and regulation of chromatin structure (5). By identifying endogenous or exogenous DNA damage, PARP-1 aggregates and bind to the site of DNA strand breaks to participate in BER. In BER, PARP-1 is catalyzed and activated by synthesis of PAR polymers by PARylation. A series of repair proteins, such as X-ray repair cross complementary combination-1 (XRCC1) and DNA polymerase β, are assembled to repair the DNA damage sites (6).

PARP transfers the ribose group of nicotinamide adenine dinucleotide (NAD+) to modify target biomolecules. This process is known as poly-ADP-ribosylation or PARylation, a reversible post-transcriptional modification that requires both PARP-1 and poly-ADP-ribose glycohydrolase (PARG) (7,8). PARylation by PARP-1 and its degradation by PARG participate in regulating DNA damage responses and biological functions (i.e., stress responses, metabolism) (9). The structure-specific recognition protein-1 is recruited to SSB in a PARP-dependent manner by interactions with the XRCC1, both of which are involved in SSB repair (10).

PARP inhibitors (PARPis) lead to cell death, notably in cells with defective DDR function, by trapping PARP-1 on damaged chromatin (11). Only three of the 17 members of the PARP enzyme family (PARP-1, PARP-2 and PARP-3) localize to the nucleus in response to early DNA damage and serve a crucial role in DDR (8). PARP1 has been implicated in the 10 hallmarks of cancer, while other PARPs modify certain cancer hallmarks, including PARP2 and PARP5a/5b, which modify cancer metabolism and replicative immortality, respectively (12).

Renal cell carcinoma (RCC) is one of the ten most common types of cancer in developed countries (13) and accounts for 2–3% of all adult tumors (14). RCC has a 2.2% incidence and 1.8% mortality rate worldwide (15). RCC is insensitive to traditional chemotherapy and radiotherapy and readily develops drug resistance; present treatment methods for localized RCC primarily include surgery, ablation and surveillance (16). Furthermore, targeted therapies for metastatic RCC are primarily focused on antiangiogenic therapy, such as inhibitors sunitinib and pazopanib, which are directed at the tyrosine kinase domain of vascular endothelial growth factor receptor (VEGFR) (17). In recent years, the combination of immunotherapy [programmed cell death 1/programmed cell death ligand (PD-L1) blockade] with tyrosine kinase inhibitors (TKIs) has increased the overall survival rate for patients with RCC (18,19). However, as a type of targeted therapy, the roles of PARPi direct to DDR in RCC treatment have not been fully explored.

Ongoing studies have been combined PARPi, antiangiogenic therapy and novel immunomodulators to improve the outcome of urinary tract tumors (20,21). In addition, studies have explored the association between DDR and prostate or bladder cancer progression and treatment (2224). To the best of our knowledge, however, there is a lack of systematic reviews of DDR, PARP and RCC. Although PARPis have been investigated in prostate cancer treatment, their use in RCC requires additional investigation and molecular classification (25). Advanced stages of certain types of cancer develop resistance against PARPis (26). Therefore, optimization of the use of PARPis is a challenge. The present review article aimed to summarize the association between DDR pathway and RCC progression and treatment.

DDR, RCC progression and precision treatment


DDR genes can be useful for predicting progression and clinical benefits of immunotherapy for ccRCC (27). Multigene tests including DDR gene provide a more comprehensive risk assessment for patients with early-onset renal cancer in comparison with the control population in genome aggregation database (28,29). DDR gene may predict future prognosis of patients with ccRCC as well as immunotherapy response (3032). Deleterious DDR gene alterations are associated with advanced ccRCC and may affect outcome of immunotherapy in ccRCC (29).

ccRCC is characterized by chromosomal instability, which is primarily caused by errors in DDR and affects DSB repair mechanisms (33). Among DSB repair mechanisms, NHEJ is an error-prone repair mechanism in which broken DNA ends are joined compared with HR repair in DNA integrity and initial DNA sequence (34). Genes encoding HR proteins include BRCA1, BRCA2, ataxia telangiectasia mutated (ATM) gene Rad3-associated kinase (ATR), BRCA1-associated RING domain 1, Bloom's syndrome (BLM) RecQ like helicase and RAD51 recombinase, and HR deficiency is defined by the inability to repair DNA damage by the normal HR repair pathway (35). Although a single gene mutation cannot result in cell death, mutations of both genes (i.e., BRCA1/2 and PARP1) lead to cell death and are considered to have a synthetic lethality effect (26).

Polymerase θ produces synthetic lethal effects with multiple DNA repair genes, such as BRCA1/2, making it key in HR-deficient cancer (36). Although PARP1 binds to DNA damage sites, PARPi may prevent PARylation, which in turn hinders recruitment of BER enzyme, impedes DNA repair and leads to DSBs and synthetic lethality in a HR-deficient mechanism (37). By contrast, the cytotoxicity of the captured PARP-DNA complexes is higher than that of the unrepaired SSBs induced by PARP inactivation, indicating that PARPi can be toxic by trapping the PARP enzyme on the DNA (38). PARP1/2 and other repair factors were activated and recruited by DNA breaks and clinical PARPis are considered to prolong the presence of PARP1/2 molecules at break sites and chromatin, called ‘trapping’ (39). Furthermore, PARP mediates DSB and NER damage repair, stability of replication forks and chromatin regulation of DNA (5).

PARPis, such as olaparib, niraparib, talazoparib and rucaparib, have been recently approved by the US Food and Drug Administration for treatment of ovarian and germline BRCA DNA repair associated mutant breast cancer (40). PARG inhibitors also promote sensitivity to radiation-induced DNA damage, inhibit the progression of replication fork and hinder the survival of cancer cells, further supporting the hypothesis that selective inhibition of PARG may prevent the survival of cancer cells (41). Therefore, although the action sites of PARG inhibitors and PARPi are different, PARPi destabilize replication forks and PARG inhibitors may complement PARPi in exacerbating the replication deficiencies of tumor cells by causing DNA damage, hindering DNA repair (42). The roles of PARP1 in DDR and synthetic lethality are shown in Fig. 1; Briefly, the DNA damage caused by SSBs and DSBs correspond to different repair pathways, while the simultaneous defects of the BER and HR repair pathways force transition to NHEJ repair, an error-prone repair mechanism that leads to cell death (Fig. 1). In addition, the DDR-associated target molecules are summarized and shown in Table I.

Table I.

DNA damage repair-associated target and molecules.

Table I.

DNA damage repair-associated target and molecules.


DNA damage repairTargetInhibitor
BERPARPRucaparib, PJ34, NU1025, Benzamide, Picolinamide


DNA damage repairTarget Inhibitor

HRATMWortmannin, KU-55933, KU-60019, AZD1390, AZ32, AZD0156
ATRBerzosertib, Elimusertib, Ceralasertib
CHK1MK8776, Prexasertib
CHK2Silmitasertib, TTP22
RAD51Amuvatinib, RI-1 (RAD51 inhibitor 1)
ALT-EJPolymerase θNovobiocin
NHEJDNA-PKNU7441, Wortmannin, PIK-75, NU7026, 6-Nitroveratraldehyde, KU-0060648, Nedisertib, AZD7648, Samotolisib
DNA ligase IVSCR7
MRE11 endonucleasePFM01

C, Other

DNA damage repairTarget Inhibitor

Not specific or clearMTH1(S)-crizotinib
Not specific (HR, NHEJ or others)TopoisomeraseDoxorubicin

[i] SSB, single-strand break; DSB, double-strand break; BER, base excision repair; PARP, poly-ADP-ribosomal polymerase; HR, homologous recombination; OGG1, 8-oxoguanine DNA glycosylase; ATM, ataxia telangiectasia mutated; ATR, ATR serine/threonine kinase; CHK, checkpoint kinase; RAD51, RAD51 recombinase; PK, protein kinase; MRE11, MRE11 homolog, double strand break repair nuclease; MTH1, nudix hydrolase 1; ALT-EJ, alternative end joining; NHEJ, non-homologous end joining.

The histone PARylation factor 1 forms a joint active site with PARP1/2 and enables recognition of the DNA damage site by PARP1/2. The latter binds to the site of DNA damage and uses NAD+ to convert receptor protein PAR into the ADP ribosomal polymer, thus facilitating the separation of PARP1/2 from the DNA break and subsequent repair (43). Following activation by DNA damage, PARP participates in genome integrity, tumor formation and stemness via the PARP1-Krüppel like factor 4 complex, thus regulating the expression of telomerase in tumor and embryonic stem cells (44). PARylation is a reversible post-transcriptional modification that requires PARP1 and PARG. By activating PARylation of target proteins, PARP regulates numerous physiological processes, including chromatin remodeling, DNA damage response, apoptosis and mitosis (45). Inhibition of PARG can also lead to synthetic lethality along with factors that inhibit DNA replication, such as checkpoint kinase 1 inhibitors. PARG inhibitors compensate for the decreased efficacy of PARPis with inhibition of DNA replication factors [i.e., Checkpoint kinase 1(CHK1) inhibitors] in ovarian cancer treatment (46). In addition to BRCA1/2 mutations, other HR repair-associated genes or predictive biomarkers are also currently explored in the early treatment of tumors by adjuvant and neoadjuvant therapy with PARPis (47).

The rs5751129 polymorphic genotype and mRNA expression levels of XRCC6 (Ku70) are associated with RCC etiology and may serve as a marker for increased susceptibility of the Taiwanese population to RCC (48). A non-invasive panel comprising circulating tumor cell and urine cellular polymorphisms of XPC (polymorphic site: rs2228001, A2815C) and XRCC1 (polymorphic site: rs25487, G1196A) showed high sensitivity for bladder and prostate cancer and RCC screening (49). The XRCC1 Arg194 allele and urinary 8-hydroxy-2 deoxyguanosine levels and total arsenic concentration are predictive factors for RCC prognosis (50). In addition, dual PARP and RAD51 inhibitor conjugates disrupt resistance mechanisms to olaparib treatment in breast cancer cells regardless of the mutation status of BRCA (51). BRCA1-associated protein 1 (BAP1) encodes a widely expressed deubiquitinase of histone H2A, resulting in increased sensitivity of bromodomain and extra-terminal inhibitors to BAP1-deficient cancer (such as cutaneous and uveal melanoma and ccRCC) (52).

Role of PARP in synthetic lethal effects and cell death

PARP is associated with necroptosis, autophagy and other types of cell death (53). PARP is cleaved by activated caspases both in vitro and in vivo, resulting into two fragments of 24 and 89 kDa, which is deemed to be a hallmark of the apoptosis (54). By contrast with caspase-3 and mutated exosites, caspase-7 uses RNA to promote proteolysis of PARP1 and other RNA-binding proteins (55). The 24 kDa DNA-binding domain may block the DNA-repair enzyme function at the divided chromatin site, while the 89 kDa fragment-containing catalytic domain cannot be activated by DNA breaks. Eventually, enzyme activity of PARP is lost, which promotes the induction of cell apoptosis (56,57). Following oxidative stress and DNA damage, PARP1 plays a dual function in regulating necrosis and autophagy. PARP1 overactivation results in ATP depletion and necrotic cell death, while its normal activation enhances autophagy via the serine threonine kinase 11/protein kinase AMP-activated catalytic subunit α2/mammalian target of rapamycin pathway, thereby increasing cell survival (58).

Loss or inactivation of PARP1 delays starvation-induced autophagy, which plays an important role in contributing to survival during nutrient starvation conditions to optimize the usage of limited energy supplies, while autophagy and PARP1 activation exert a pro-survival effect following nutrient deprivation (59). In addition to autophagy and apoptosis, necroptosis caused by tumor necrosis factor (TNF)-related apoptosis-inducing ligand, which mediates the receptor-interacting serine/threonine-protein kinase (RIPK) 1/RIPK3-dependent activation of PARP1 pathway, is associated with liver injury (60). Unlike the induction of apoptosis, necrosis and other forms of cell death, parthanatos is a PARP1-dependent and caspase-independent cell-death pathway (61). During PARP1-mediated cell death, mitochondrial protein apoptosis-inducing factor is released and transferred to the nucleus (62). In BRCA wild-type) ovarian cancer, PARP inhibition promotes ferroptosis by suppressing solute carrier family 7 member 11 and synergizing with ferroptosis inducers (63). Antioxidants and the PARP1 inhibitor olaparib rescue the death of RCC cells triggered by zafirlukast, a cysteinyl leukotriene receptor 1 antagonist, dependent on that of hypoxia-inducible factor (HIF)-2α (64). Therefore, the understanding of the association between PARP and forms of cell death as well as its role in gene stability is key for design of novel chemotherapeutic drugs for various types of cancer.

Certain PARP family enzymes exhibit poly-catalyzed enzymatic activity, whereas others are characterized by mono-catalyzed enzymatic activity (Table II) (65). PARPis competitively bind to the NAD+ binding sites of the PARP1/2 enzymes and inhibit PARylation, improving the clinical benefits in BRCA mutant tumors (Table I). The use of the oral inhibitor of PARP1/2 olaparib has been approved by FDA. This compound is primarily used for treatment of patients with ovarian cancer containing the BRCA1/2 mutation (66). Patients with breast and ovarian cancer who possess BRCA1/2 mutations or deletions may benefit from PARP1 and PARP2 inhibitors (67). Ovarian cancer cells with higher expression of NADP+ are more sensitive to PARPi (68). Synthetic lethality enables PARPis to achieve their desired efficacy in clinical trials (26,69,70). Presently, the PARPi is used in tumors with BRCA1/2 mutations, such as those derived from breast and ovarian cancer, and ongoing research is exploited beyond germline BRCA mutations to identify suitable biomarkers to predict treatment response (71).

Table II.

PARP-associated catalyzed enzymatic activity and inhibitors.

Table II.

PARP-associated catalyzed enzymatic activity and inhibitors.

PARP family memberCatalyzed enzymatic activityInhibitor
PARP1PolyTalazoparib, Olaparib, Rucaparib, Veliparib, Iniparib, Fluzoparib, Pamiparib, Stenoparib, Venadaparib, Niraparib, AG-14361, NMS-P118, Picrasidine M, BYK204165, ME0328, E7449, 4-Hydroxyquinazoline, Mefuparib
PARP2PolyVenadaparib, Pamiparib, Stenoparib, A-966492, E7449, Niraparib, Olaparib, Veliparib, BYK204165, UPF 1069, Mefuparib
PARP3MonoME0328, Niraparib
Tankyrase-1Poly/OligoXAV-939, MN64, RK-287107, G007-LK, E7449, Mefuparib
Tankyrase-2Poly/OligoXAV-939, MN64, RK-287107, NVP-TNKS656, WIKI4, G007-LK, E7449, Mefuparib
PARP7MonoRBN012759, GeA-69
PARP14MonoAtamparib, PARP14 inhibitor H10
PARP ActiviatorNot applicableLicochalcone D, 4′,5,7-Trimethoxyflavone, Ferruginol, Hellebrigenin, Polyporenic acid C

[i] PARP, poly (ADP)-ribosomal polymerase.

As PARP trapping activity may exceed the inhibitory potential of PARylation reactions, the clinical exploration processes for the antitumor activity of PARPis are different (72). Moreover, the supply domain of PARP1 binds to the nicotinamide-riboni site of NAD+; PARPis simulate the nicotinamide structural domain and competitively bind the Ni binding site of PARP, which leads to partial binding to the receptor binding site of PARP (73). As NAD+ competitors are prone to off-target effects, a novel inhibitor of PARP1 that specifically targets the histone-dependent PARP1 activation pathway has been developed to overcome the limits of NAD-like PARP1 inhibitors, which exhibit high specificity to PARP1 and a potentially potent therapeutic effect on urological tumors (74). In addition, classical NAD-like PARP1 inhibitors may inhibit the survival of normal kidney epithelial cells at high concentrations, whereas novel non-NAD-like PARP1 inhibitors are only active against malignant cells (75). As PARP activity is associated with various types of cell death, development of PARP activators that contribute to tumor cell death is being investigated (Table II).

Renal cancer and precision therapy

RCCs are classified into three primary histopathological classifications as follows: ccRCC, pRCC and chRCC, with a proportion of incidence 70–75%, 10–16% and 5%, respectively (76). Non-ccRCC (nccRCC) include the pRCC, chRCC, unclassified, collecting duct, and translocation carcinoma (77). As most prevalent subtype of RCC, Approximately 70% of the ccRCC cases are are linked to the mutation or inactivation of a tumor suppressor gene, namely von Hippel-Lindau (VHL), resulting in activation of the HIF/VEGF pathway (78). TKIs targeting VEGFR are key RCC treatment drugs (18). VEGFR-based TKIs, such as sunitinib and pazopanib, have been the mainstay of treatment for patients with advanced RCC. However, RCC cells are prone to develop drug resistance to VEGFR-TKIs, which limits the efficacy of targeted therapy (79). Recently, several therapeutic options have been approved (immunotherapy and immunotherapy/TKIs) for first-line treatment of metastatic ccRCC, such as axtinib + pembrolizumab or avelumab, nivolumab + cabozantinib or ipilimumab and pembrolizumab + lenvatinib (Fig. 2) (19).

To date, various abnormal gene indicators of RCC have been detected and evaluated. The mutations of polybromo 1 (PBRM1), BRCA1-associated protein 1 and lysine demethylase 5C genes affect the outcome of targeted therapy with sunitinib in patients with metastatic ccRCC (80). Global tumor cell expression profile may be altered by loss of PBRM1 in ccRCC, thereby influencing the responsiveness to immune checkpoint therapy (81). The increase in expression levels of p53 and alteration of targets of the rapamycin pathway, such as neurofibromin 1 and phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit α, may be associated with resistance of patients following first-line VEGF-directed therapy (82). Cyclin-dependent kinase inhibitor 2A and MET proto-oncogene receptor tyrosine kinase are the most frequently altered somatic genes in nccRCC tumors and are treated by cabozantinib (83).

In a patient with chRCC, biallelic TSC complex subunit 2 mutations have been associated with a notable response to temsirolimus (84). Atezolizumab and bevacizumab have been shown to be safe and produce an objective response in patients with RCC and variant histology or >20% sarcomatoid differentiation, particularly in patients with PD-L1-positive tumors (85). Belzutifan, a HIF-2 inhibitor, has been approved by the FDA for treatment of patients with VHL syndrome-associated RCC that do not require immediate surgery (86). However, in clinical trials, only some ccRCC patients appear to be benefit from the HIF-2 inhibitors, and using intact p53 pathway status may be premature to predict sensitivity ccRCC patients to HIF-2 inhibitors (87). Compared with normal kidney cells, benzo[4]helicenium shows specific killing efficiency against RCC, selectively damaging mitochondria and DNA in RCC cancer cells, providing a potential targeted drug for RCC precision therapy (88).

DDR genes and precision treatment of renal cancer

Resistance to targeted therapies remains a key obstacle in clinical treatment of cancer. Sunitinib induces genomic instability of RCC cells by affecting the interaction of microtubule-associated protein 1A/1B-light chain 3-II and PARP1 (89). As a PARPi, olaparib reverses drug resistance to sorafenib in liver cancer (90). A total of 27–32% of RCC tissue samples have mutations in HR genes, while PARPi agents (such as niraparib, talazoparib and rucaparib) that target DDR mutations may be effective treatment options for RCC (91). Due to increased PARP1 expression and decreased PARG levels, ccRCC is accompanied by increased levels of poly(ADPribose) (pADPr). The development of ccRCC is associated with accumulation of pADPr (75). VHL-deficient RCC is associated with downregulation of DNA repair induced by hypoxia, conferring increased sensitivity to PARPis (92). Impaired DNA repair ability, which is associated with the BRCA1A complex, sensitizes folliculin-deficient RCC cells to olaparib treatment (93). Therefore, it is desirable to explore the combination effect between VEGFR-TKIs and PARPi in RCC (Fig. 3). The PARP and PARPi function in modulation of RCC tumor cell death was shown in Fig. 3.

In addition to DNA damage, PARPs serve metabolic regulatory roles and are involved in obesity, which modulates carbohydrate and lipid metabolism and guides pathologically metabolic abnormalities (94). PARPs act as cofactors of nuclear receptors or transcription factors that are activated in a lipid-responsive manner. PARPs modulate lipid metabolism and homeostasis, while activation PARP disrupts lipid metabolism signal (95). As aforementioned, ccRCC is often associated with VHL mutations or deletions, which affect its metabolic properties and enhances sensitivity to glutathione peroxidase 4 inhibitors that induce ferroptosis (96). Glutaminase inhibitors inhibit pyrimidine synthesis and increase levels of reactive oxygen species in VHL-deficient RCC cells, leading to DNA replication stress and suppression of VHL−/− RCC cell proliferation, while olaparib, a PARPi, inhibits proliferation of these cells by acting in a synergistic mechanism with glutaminase inhibitors (97). This combined treatment supports the development of novel treatment strategies that target VHL-deficient RCC and chemoresistant ovarian cancers (97,98). By utilizing hypoxia-inducible lipid droplet associated protein, the VHL/HIF-2α pathway may induce ferroptosis by upregulating lipid peroxidation levels (99).

The Warburg effect, demonstrated by increased glycolytic intermediate labeling, decreased pyruvate dehydrogenase flow and decreased tricarboxylic acid cycle labeling, has been observed in various primary ccRCC cases (100). By regulating PARP1 expression, lipid metabolism-associated drugs simvastatin and tanshinone I inhibit proliferation of melanoma and renal tumour cells (101). Therefore, PARP inhibition may exert a synergistic inhibitory effect on tumor growth of ccRCC with other metabolic inhibitory molecules (97). The gene mutations of RCC are heterozygous both at the primary site and metastatic lesions, but the distant metastatic lesions may exihibit more significant growth and invasion phenotype, which may be associated with the function of the DDR response. Therefore, the primary site, and, particularly the metastatic lesions, should be considered for the evaluation of metastatic RCC.

RCC is non-sensitive to chemoradiotherapy; however, its mechanism remains unknown. The increase of PARP1 in RCC cells leads to radioresistance and certain PARP1 inhibitors enhance sensitivity of radiotherapy in human RCC xenograft and head and neck squamous cell carcinoma cell models (102,103). DAB adaptor protein 2 interactive protein (DAB2IP) can degrade PARP1 by forming a complex with PARP1 and E3 ligases, causing DAB2IP deficient RCC cells acquire resistance to ionizing radiation (102). Inhibition of DNA repair by radiation therapy combined with veliparib accelerates induction of tumor cell senescence and induces expression of immune stimulators to activate cytotoxic T lymphocytes and mediate antitumor response (104). Patients with ccRCC with high exosome component 1 show poor prognosis; exosome component 1 cleaves single-stranded DNA and sensitizes human ccRCC cells to PARPis (105).

Increased progression-free survival has been noted in patients with advanced RCC treated with first-line nivolumab combined with cabozantinib compared with those treated with sunitinib (106). PARP1 low expression protein levels are associated with higher patient overall survival following treatment with immune checkpoint inhibitors (ICIs) (107). The overall survival and progression-free survival of patients with PBR-mutated 1 (PBRM1) ccRCC treated with nivolumab were significantly increased in the PARP1-low group compared with that noted in the PARP1-high expression (107). Inactivation of PBRM1 occurs in 40% of ccRCC cases and contributes to a synthetic lethal effect for PARP and ATR inhibitors, which provides a basis for evaluating the efficacy of these inhibitors in treatment of patients with PBRM1-deficient cancer (108). DEAD/H-box helicase 11 may be a novel biomarker for patients with RCC resistance to TKIs and immunotherapy and may predict PARPi sensitivity in RCC (109).

In collecting duct RCC (CDRCC), expression levels of baculoviral IAP repeat containing 5, pituitary tumor-transforming gene 1 regulator of sister chromatid separation, centromere protein F and cyclin-dependent kinase inhibitor 3 [specific marker genes of cancer stem cells (CSCs)] are associated with poor, while inhibitors of PARP, histone deacetylase 2 and fibroblast growth factor receptor are effective against CSCs and may serve as potential therapeutic options for CDRCC (110). ATM is a key tumor suppressor gene found in almost 3% of RCC and is involved in HR repair (Fig. 1). ATM mutation may affect RCC tumor response to veliparib (a PARPi), which produces months of disease control, decreased levels of lactate dehydrogenase and improved performance status, as demonstrated in a case report of pRCC (111). A case for niraparib to sorafenib-axitinib-everolimus-resistance metastatic ccRCC with BAP1-Frame shift mutation has achieved a partial response and lasted for 5 months (112). Although has not been formally clinically tested, to the best of our knowledge, the above cases provide examples for the use of PARPi in the treatment of certain type of RCC. By producing fumarate, fumarate hydratase (FH) was defined as DNA repair required in NHEJ in cells (113). Inactivation or germline mutations of FH lead to hereditary leiomyomatosis and RCC (HLRCC), while loss of FH and accumulation of fumarate lead to decreased G2 checkpoint, which increases the possibility of endogenous DNA damage (114). Succinate dehydrogenase (SDH)-related hereditary paraganglioma and pheochromocytoma is another hereditary cancer syndrome associated with mutations in SDH. These mutations suppress the HR DNA repair pathway, thus rendering tumor cells susceptible to synthetic lethality by PARPi (115). Metabolites associated with germline mutations of FH and SDH genes (SDHA, SDHB, SDHC and SDHD) suppress HR repair pathway, conferring sensitivity to PARPis in vivo experiment or in clinical trials (116,117).

Since PARP is associated with various forms of cell death, such as apoptosis, autophagy and necroptosis, numerous PARP activators have been developed that exhibit inhibitory effects on RCC cells. For example, tumor protein p53-inducible nuclear protein 2 (TP53INP2) activates expression of PARP in patients with ccRCC and the overexpression of TP53INP2 inhibits ccRCC cell proliferation, migration and invasion (118). The induction of apoptosis in RCC cells is accompanied by elevation of reactive oxygen species (ROS) levels and induction of cleaved-PARP expression (119). PARP activation also plays a key role in necroptosis induced by glutamate, which is blocked by necrostatin-1 (120). Oridonin, a key ingredient of traditional Chinese medicine Rabdosia rubescens, enhances cytotoxicity of 5-fluorouracil in RCC cells by enhancing activity of PARP1 and inducing necroptosis (121). By increasing ROS levels, decreasing pro-PARP and increasing cleaved PARP expression levels, shikonin, a component of traditional Chinese medicine Comfrey, triggers programmed death of different types of RCC cell (122).

DDR and renal protection

Inhibition of angiogenesis may be associated with cardiovascular and kidney toxicity (123,124), as well as liver injury (125). Genetic deletion or suppression of PARP1 appears to be protective against toxic insult in various organs (i.e., hemodynamic dysfunction, multiple organ failure in patients with sepsis) (126,127). Pharmacological suppression or genetic deletion of PARP1 markedly decreases cisplatin-induced kidney injury, suggesting that pharmacological inhibition of PARP may be a promising method for inhibiting nephropathy caused by cisplatin (128). By attenuating the intrarenal inflammatory cascade, amelparib, a PARPi, exerts favorable effects in an mice model of ischemic acute kidney injury and promotes hypoxic HK-2 cell proliferation (129). Olaparib, a clinically approved PARPi for the treatment of HR-deficient tumors, improves organ function, suppresses inflammatory responses and expedites wound healing in severe burn injury (130). Therefore, genetic deletion or suppression of PARP1 may have a protective effect in various organs, suggesting the detoxification and synergism effect of PARPis on RCC treatment. Although there is no evidence to suggest that accumulation of renal toxicity is associated with occurrence of RCC, inhibition of PARP has a key protective effect on the kidney and its role in the prevention or treatment of RCC is worth investigation.

Future directions

Currently, the primary indications for the use of PARPis include tumors with BRCA1/2 mutation (131). However, identification of additional predictive biomarkers is key to determine the treatment options according to the RCC molecular characteristics (132). Drugs that promote HR repair defects in tumor cells (i.e., PI3K inhibitors, cyclin-dependent kinase inhibitors) may increase sensitivity to PARPis (133136). As a specific polymerase θ inhibitor, novobiocin is combined with PARPi in treatment of HR-deficient tumors, as well in tumors that have acquired PARPi resistance (137). In addition, with the wider clinical use of PARPi, whether long-term inhibition of PARP activity may lead to mutations or protection in normal cells, or other unknown negative or positive effects, will more thoroughly be verified.

In ovarian cancer specimens, PARP1 and PD-L1 are negatively correlated (138). PARPi upregulates expression of PD-L1 by inactivating GSK3β in breast tumors and the antitumor effect of PARPi combined with PD-L1 is significantly increased in vivo compared with that of PD-L1 treatment alone (139). In immunotherapy, however, cytotoxic T lymphocyte-associated protein 4 antibody but not PD-1/PD-L1 blocker synergistically causes immune-mediated tumor clearance and survival benefit with PARPi in hereditary ovarian cancer (140). Therefore, combination of PARPi and ICIs in treatment of RCC should be investigated in future.

In addition to immunotherapy, development of synthetic lethal associated targets [such as protein kinase, membrane associated tyrosine/threonine 1)/cyclin E1 and e-cadherin/ROS1 inhibitor] may offer novel directions for tumor therapy (141,142). In addition, dual PARP and RAD51 or other DNA repair target inhibitor conjugates have the potential to overcome resistance mechanisms to PARPi. The positive results of inhibition of PARP in other DDR-associated genes, such as PALB2 (partner and localized of BRCA2) in prostate cancer, may benefit further explorations of PARP inhibition in RCC treatment. Therefore, DDR genes are key tumor targets involved in various forms of cell death. The application of DDR inhibitors (such as PARPi) and other targeted, immunotherapy and tumor metabolism-associated drugs in RCC should be explored in future.


RCC incidence and mortality rate are high worldwide and lack useful immunotherapy options. The enzymatic activity or expression level of DDR genes, particularly PARP1, may serve as potential tumor therapeutic targets. Moreover, PARP1 may serve as a key biological marker to predict the therapeutic effect of ICIs and evaluate prognosis of patients with ccRCC. The role of DDR pathways in RCC progression may provide potential therapeutic targets for treatment of certain types of RCC.


Not applicable.


The present study was supported by the National Natural Science Foundation of China (grant no. 81803576) and Shenzhen Futian District Public Health Research Project (grant nos. FTWS2021073 and FTWS2020026).

Authors' contributions

YCL, FCT, ZCL, HXZ, CHC, CL, YFY and ZHH contributed to manuscript writing. CHC, CL, YFY and ZHH conceptualized the study. YCL constructed tables and figures. FCT, ZBL, HZH and YCL critically revised the manuscript. All authors have read and approved the final manuscript. Data authentication is not applicable.

Availability of data and materials

Not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.





DNA damage repair


poly (ADP-ribose) polymerase


poly(ADP-ribose) glycohydrolase


nicotinamide adenine dinucleotide


non-clear cell renal cell carcinoma


papillary renal cell carcinoma


chromophobe renal cell carcinoma


overall survival


hereditary leiomyomatosis and renal cell cancer


fumarate hydratase


succinate dehydrogenase-related hereditary paraganglioma and pheochromocytoma


collecting duct renal cell carcinoma


immune checkpoint inhibitor


programmed death ligand 1


vascular endothelial growth factor receptor


ataxia telangiectasia mutated


von Hippel-Lindau


hypoxia-inducible factor


tyrosine kinase inhibitor


reactive oxygen species


polybromo 1


single-strand break


X-ray repair cross complementary combination-1


nucleotide excision repair


base excision repair


homologous recombination


non-homologous end joining


double-strand break


receptor-interacting serine/threonine-protein kinase


tumor protein p53-inducible nuclear protein 2



Abbotts R and Wilson DR: Coordination of DNA single strand break repair. Free Radic Biol Med. 107:228–244. 2017. View Article : Google Scholar : PubMed/NCBI


Anand SK, Sharma A, Singh N and Kakkar P: Entrenching role of cell cycle checkpoints and autophagy for maintenance of genomic integrity. DNA Repair (Amst). 86:1027482020. View Article : Google Scholar : PubMed/NCBI


Oh JM and Myung K: Crosstalk between different DNA repair pathways for DNA double strand break repairs. Mutat Res Genet Toxicol Environ Mutagen. 873:5034382022. View Article : Google Scholar : PubMed/NCBI


Lavrik OI: PARPs' impact on base excision DNA repair. DNA Repair (Amst). 93:1029112020. View Article : Google Scholar : PubMed/NCBI


Ray CA and Nussenzweig A: The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol. 18:610–621. 2017. View Article : Google Scholar : PubMed/NCBI


Koczor CA, Saville KM, Andrews JF, Clark J, Fang Q, Li J, Al-Rahahleh RQ, Ibrahim M, McClellan S, Makarov MV, et al: Temporal dynamics of base Excision/Single-Strand break repair protein complex assembly/disassembly are modulated by the PARP/NAD+/SIRT6 axis. Cell Rep. 37:1099172021. View Article : Google Scholar : PubMed/NCBI


Richard IA, Burgess JT, O'Byrne KJ and Bolderson E: Beyond PARP1: The potential of other members of the poly (ADP-Ribose) polymerase family in DNA repair and cancer therapeutics. Front Cell Dev Biol. 9:8012002021. View Article : Google Scholar : PubMed/NCBI


Covarrubias AJ, Perrone R, Grozio A and Verdin E: NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 22:119–141. 2021. View Article : Google Scholar : PubMed/NCBI


Gupte R, Liu Z and Kraus WL: PARPs and ADP-ribosylation: Recent advances linking molecular functions to biological outcomes. Genes Dev. 31:101–126. 2017. View Article : Google Scholar : PubMed/NCBI


Gao Y, Li C, Wei L, Teng Y, Nakajima S, Chen X, Xu J, Leger B, Ma H, Spagnol ST, et al: SSRP1 cooperates with PARP and XRCC1 to facilitate single-strand DNA break repair by chromatin priming. Cancer Res. 77:2674–2685. 2017. View Article : Google Scholar : PubMed/NCBI


Prokhorova E, Zobel F, Smith R, Zentout S, Gibbs-Seymour I, Schutzenhofer K, Peters A, Groslambert J, Zorzini V, Agnew T, et al: Serine-linked PARP1 auto-modification controls PARP inhibitor response. Nat Commun. 12:40552021. View Article : Google Scholar : PubMed/NCBI


Demeny MA and Virag L: The PARP enzyme family and the hallmarks of cancer part 1. Cell intrinsic hallmarks. Cancers (Basel). 13:20422021. View Article : Google Scholar : PubMed/NCBI


Shaw G: The silent disease. Nature. 537 (Suppl):S98–S99. 2016. View Article : Google Scholar : PubMed/NCBI


Linehan WM and Ricketts CJ: The Cancer Genome Atlas of renal cell carcinoma: Findings and clinical implications. Nat Rev Urol. 16:539–552. 2019. View Article : Google Scholar : PubMed/NCBI


Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI


Mao W, Wang K, Wu Z, Xu B and Chen M: Current status of research on exosomes in general, and for the diagnosis and treatment of kidney cancer in particular. J Exp Clin Cancer Res. 40:3052021. View Article : Google Scholar : PubMed/NCBI


Lai Y, Zeng T, Liang X and Wu W, Zhong F and Wu W: Cell death-related molecules and biomarkers for renal cell carcinoma targeted therapy. Cancer Cell Int. 19:2212019. View Article : Google Scholar : PubMed/NCBI


Xiong W, Zhang B, Yu H, Zhu L, Yi L and Jin X: RRM2 Regulates sensitivity to sunitinib and PD-1 blockade in renal cancer by stabilizing ANXA1 and activating the AKT pathway. Adv Sci (Weinh). 8:e21008812021. View Article : Google Scholar : PubMed/NCBI


Popovic M, Matovina-Brko G, Jovic M and Popovic LS: Immunotherapy: A new standard in the treatment of metastatic clear cell renal cell carcinoma. World J Clin Oncol. 13:28–38. 2022. View Article : Google Scholar : PubMed/NCBI


Criscuolo D, Morra F, Giannella R, Visconti R, Cerrato A and Celetti A: New combinatorial strategies to improve the PARP inhibitors efficacy in the urothelial bladder Cancer treatment. J Exp Clin Cancer Res. 38:912019. View Article : Google Scholar : PubMed/NCBI


Yuasa T, Urasaki T and Oki R: Recent advances in medical therapy for urological cancers. Front Oncol. 12:7469222022. View Article : Google Scholar : PubMed/NCBI


Yin M, Grivas P, Wang QE, Mortazavi A, Emamekhoo H, Holder SL, Drabick JJ, Woo MS, Pal S, Vasekar M, et al: Prognostic value of DNA damage response genomic alterations in Relapsed/Advanced urothelial cancer. Oncologist. 25:680–688. 2020. View Article : Google Scholar : PubMed/NCBI


Zhang W, van Gent DC, Incrocci L, van Weerden WM and Nonnekens J: Role of the DNA damage response in prostate cancer formation, progression and treatment. Prostate Cancer Prostatic Dis. 23:24–37. 2020. View Article : Google Scholar : PubMed/NCBI


Chakraborty G, Armenia J, Mazzu YZ, Nandakumar S, Stopsack KH, Atiq MO, Komura K, Jehane L, Hirani R, Chadalavada K, et al: Significance of BRCA2 and RB1 Co-loss in aggressive prostate cancer progression. Clin Cancer Res. 26:2047–2064. 2020. View Article : Google Scholar : PubMed/NCBI


Rimar KJ, Tran PT, Matulewicz RS, Hussain M and Meeks JJ: The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies. Cancer-Am Cancer Soc. 123:1912–1924. 2017.PubMed/NCBI


Lord CJ and Ashworth A: PARP inhibitors: Synthetic lethality in the clinic. Science. 355:1152–1158. 2017. View Article : Google Scholar : PubMed/NCBI


Guo E, Wu C, Ming J, Zhang W, Zhang L and Hu G: The clinical significance of DNA damage repair signatures in clear cell renal cell carcinoma. Front Genet. 11:5930392020. View Article : Google Scholar : PubMed/NCBI


Hartman TR, Demidova EV, Lesh RW, Hoang L, Richardson M, Forman A, Kessler L, Speare V, Golemis EA, Hall MJ, et al: Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer. Sci Rep. 10:135182020. View Article : Google Scholar : PubMed/NCBI


Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, et al: The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 581:434–443. 2020. View Article : Google Scholar : PubMed/NCBI


Peng L, Liang J, Wang Q and Chen G: A DNA Damage repair gene signature associated with immunotherapy response and clinical prognosis in clear cell renal cell carcinoma. Front Genet. 13:7988462022. View Article : Google Scholar : PubMed/NCBI


Meng H, Jiang X, Cui J, Yin G, Shi B, Liu Q, Xuan H and Wang Y: Genomic analysis reveals novel specific metastatic mutations in Chinese clear cell renal cell carcinoma. Biomed Res Int. 2020:24951572020. View Article : Google Scholar : PubMed/NCBI


Ged Y, Chaim JL, DiNatale RG, Knezevic A, Kotecha RR, Carlo MI, Lee CH, Foster A, Feldman DR, Teo MY, et al: DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy. J Immunother Cancer. 8:e0002302020. View Article : Google Scholar : PubMed/NCBI


Tapia-Laliena MA, Korzeniewski N, Pena-Llopis S, Scholl C, Frohling S, Hohenfellner M, Duensing A and Duensing S: Cullin 5 is a novel candidate tumor suppressor in renal cell carcinoma involved in the maintenance of genome stability. Oncogenesis. 8:42019. View Article : Google Scholar : PubMed/NCBI


Bhattacharjee S and Nandi S: Choices have consequences: The nexus between DNA repair pathways and genomic instability in cancer. Clin Transl Med. 5:452016. View Article : Google Scholar : PubMed/NCBI


Huang R and Zhou PK: DNA damage repair: Historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Signal Transduct Target Ther. 6:2542021. View Article : Google Scholar : PubMed/NCBI


Schrempf A, Slyskova J and Loizou JI: Targeting the DNA repair enzyme polymerase theta in cancer therapy. Trends Cancer. 7:98–111. 2021. View Article : Google Scholar : PubMed/NCBI


Horton JK, Stefanick DF, Prasad R, Gassman NR, Kedar PS and Wilson SH: Base excision repair defects invoke hypersensitivity to PARP inhibition. Mol Cancer Res. 12:1128–1139. 2014. View Article : Google Scholar : PubMed/NCBI


Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S and Pommier Y: Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 72:5588–5599. 2012. View Article : Google Scholar : PubMed/NCBI


Shao Z, Lee BJ, Rouleau-Turcotte E, Langelier MF, Lin X, Estes VM, Pascal JM and Zha S: Clinical PARP inhibitors do not abrogate PARP1 exchange at DNA damage sites in vivo. Nucleic Acids Res. 48:9694–9709. 2020. View Article : Google Scholar : PubMed/NCBI


Rao PD, Sankrityayan H, Srivastava A, Kulkarni YA, Mulay SR and Gaikwad AB: ‘PARP'ing fibrosis: Repurposing poly (ADP ribose) polymerase (PARP) inhibitors. Drug Discov Today. 25:1253–1261. 2020. View Article : Google Scholar : PubMed/NCBI


Houl JH, Ye Z, Brosey CA, Balapiti-Modarage L, Namjoshi S, Bacolla A, Laverty D, Walker BL, Pourfarjam Y, Warden LS, et al: Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death. Nat Commun. 10:56542019. View Article : Google Scholar : PubMed/NCBI


Slade D: PARP and PARG inhibitors in cancer treatment. Genes Dev. 34:360–394. 2020. View Article : Google Scholar : PubMed/NCBI


Suskiewicz MJ, Zobel F, Ogden T, Fontana P, Ariza A, Yang JC, Zhu K, Bracken L, Hawthorne WJ, Ahel D, et al: HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation. Nature. 579:598–602. 2020. View Article : Google Scholar : PubMed/NCBI


Hsieh MH, Chen YT, Chen YT, Lee YH, Lu J, Chien CL, Chen HF, Ho HN, Yu CJ, Wang ZQ and Teng SC: PARP1 controls KLF4-mediated telomerase expression in stem cells and cancer cells. Nucleic Acids Res. 45:10492–10503. 2017. View Article : Google Scholar : PubMed/NCBI


Miwa M and Masutani M: PolyADP-ribosylation and cancer. Cancer Sci. 98:1528–1535. 2007. View Article : Google Scholar : PubMed/NCBI


Pillay N, Tighe A, Nelson L, Littler S, Coulson-Gilmer C, Bah N, Golder A, Bakker B, Spierings D, James DI, et al: DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-Ribose) glycohydrolase inhibitors. Cancer Cell. 35:519–533. 2019. View Article : Google Scholar : PubMed/NCBI


Pilie PG, Gay CM, Byers LA, O'Connor MJ and Yap TA: PARP inhibitors: Extending benefit beyond BRCA-mutant cancers. Clin Cancer Res. 25:3759–3771. 2019. View Article : Google Scholar : PubMed/NCBI


Chang WS, Ke HL, Tsai CW, Lien CS, Liao WL, Lin HH, Lee MH, Wu HC, Chang CH, Chen CC, et al: The role of XRCC6 T-991C functional polymorphism in renal cell carcinoma. Anticancer Res. 32:3855–3860. 2012.PubMed/NCBI


Wu C, Xu C, Wang G, Zhang D and Zhao X: Noninvasive circulating tumor cell and urine cellular XPC (rs2228001, A2815C) and XRCC1 (rs25487, G1196A) polymorphism detection as an effective screening panel for genitourinary system cancers. Transl Cancer Res. 8:2803–2812. 2019. View Article : Google Scholar : PubMed/NCBI


Hsueh YM, Lin YC, Chen WJ, Huang CY, Shiue HS, Pu YS, Chen CH and Su CT: The polymorphism XRCC1 Arg194Trp and 8-hydroxydeoxyguanosine increased susceptibility to arsenic-related renal cell carcinoma. Toxicol Appl Pharmacol. 332:1–7. 2017. View Article : Google Scholar : PubMed/NCBI


Malka MM, Eberle J, Niedermayer K, Zlotos DP and Wiesmuller L: Dual PARP and RAD51 inhibitory drug conjugates show synergistic and selective effects on breast cancer cells. Biomolecules. 11:9812021. View Article : Google Scholar : PubMed/NCBI


Xu YY, Ren ZL, Liu XL, Zhang GM, Huang SS, Shi WH, Ye LX, Luo X, Liu SW, Li YL and Yu L: BAP1 loss augments sensitivity to BET inhibitors in cancer cells. Acta Pharmacol Sin. 43:1803–1815. 2022. View Article : Google Scholar : PubMed/NCBI


Li X, Zhang Z, Fan B, Li Y, Song D and Li GY: PARP-1 Is a potential marker of retinal photooxidation and a key signal regulator in retinal light injury. Oxid Med Cell Longev. 2022:68813222022. View Article : Google Scholar : PubMed/NCBI


Li X and Darzynkiewicz Z: Cleavage of Poly(ADP-ribose) polymerase measured in situ in individual cells: Relationship to DNA fragmentation and cell cycle position during apoptosis. Exp Cell Res. 255:125–132. 2000. View Article : Google Scholar : PubMed/NCBI


Desroches A and Denault JB: Caspase-7 uses RNA to enhance proteolysis of poly(ADP-ribose) polymerase 1 and other RNA-binding proteins. Proc Natl Acad Sci USA. 116:21521–21528. 2019. View Article : Google Scholar : PubMed/NCBI


Koh DW, Dawson TM and Dawson VL: Mediation of cell death by poly(ADP-ribose) polymerase-1. Pharmacol Res. 52:5–14. 2005. View Article : Google Scholar : PubMed/NCBI


D'Amours D, Sallmann FR, Dixit VM and Poirier GG: Gain-of-function of poly(ADP-ribose) polymerase-1 upon cleavage by apoptotic proteases: Implications for apoptosis. J Cell Sci. 114:3771–3778. 2001. View Article : Google Scholar : PubMed/NCBI


Huang Q and Shen HM: To die or to live: The dual role of poly(ADP-ribose) polymerase-1 in autophagy and necrosis under oxidative stress and DNA damage. Autophagy. 5:273–276. 2009. View Article : Google Scholar : PubMed/NCBI


Rodriguez-Vargas JM, Ruiz-Magana MJ, Ruiz-Ruiz C, Majuelos-Melguizo J, Peralta-Leal A, Rodriguez MI, Munoz-Gamez JA, de Almodovar MR, Siles E, Rivas AL, et al: ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy. Cell Res. 22:1181–1198. 2012. View Article : Google Scholar : PubMed/NCBI


Jouan-Lanhouet S, Arshad MI, Piquet-Pellorce C, Martin-Chouly C, Le Moigne-Muller G, Van Herreweghe F, Takahashi N, Sergent O, Lagadic-Gossmann D, Vandenabeele P, et al: TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation. Cell Death Differ. 19:2003–2014. 2012. View Article : Google Scholar : PubMed/NCBI


Zhou Y, Liu L, Tao S, Yao Y, Wang Y, Wei Q, Shao A and Deng Y: Parthanatos and its associated components: Promising therapeutic targets for cancer. Pharmacol Res. 163:1052992021. View Article : Google Scholar : PubMed/NCBI


Wang Y, Kim NS, Haince JF, Kang HC, David KK, Andrabi SA, Poirier GG, Dawson VL and Dawson TM: Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos). Sci Signal. 4:a202011. View Article : Google Scholar


Hong T, Lei G, Chen X, Li H, Zhang X, Wu N, Zhao Y, Zhang Y and Wang J: PARP inhibition promotes ferroptosis via repressing SLC7A11 and synergizes with ferroptosis inducers in BRCA-proficient ovarian cancer. Redox Biol. 42:1019282021. View Article : Google Scholar : PubMed/NCBI


Wolf C, Smith S and van Wijk SJL: Zafirlukast Induces VHL- and HIF-2α-dependent oxidative cell death in 786-O clear cell renal carcinoma cells. Int J Mol Sci. 23:35672022. View Article : Google Scholar : PubMed/NCBI


Manco G, Lacerra G, Porzio E and Catara G: ADP-Ribosylation Post-translational modification: An overview with a focus on RNA biology and new pharmacological perspectives. Biomolecules. 12:4432022. View Article : Google Scholar : PubMed/NCBI


Deeks ED: Olaparib: First global approval. Drugs. 75:231–240. 2015. View Article : Google Scholar : PubMed/NCBI


Kummar S, Chen A, Parchment RE, Kinders RJ, Ji J, Tomaszewski JE and Doroshow JH: Advances in using PARP inhibitors to treat cancer. BMC Med. 10:252012. View Article : Google Scholar : PubMed/NCBI


Bian C, Zhang C, Luo T, Vyas A, Chen SH, Liu C, Kassab MA, Yang Y, Kong M and Yu X: NADP+ is an endogenous PARP inhibitor in DNA damage response and tumor suppression. Nat Commun. 10:6932019. View Article : Google Scholar : PubMed/NCBI


Murata S, Zhang C, Finch N, Zhang K, Campo L and Breuer EK: Predictors and modulators of synthetic lethality: An update on PARP inhibitors and personalized medicine. Biomed Res Int. 2016:23465852016. View Article : Google Scholar : PubMed/NCBI


Zatreanu D, Robinson H, Alkhatib O, Boursier M, Finch H, Geo L, Grande D, Grinkevich V, Heald RA, Langdon S, et al: Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat Commun. 12:36362021. View Article : Google Scholar : PubMed/NCBI


Boussios S, Rassy E, Moschetta M, Ghose A, Adeleke S, Sanchez E, Sheriff M, Chargari C and Pavlidis N: BRCA mutations in ovarian and prostate cancer: Bench to bedside. Cancers (Basel). 14:36362021.


Min A and Im SA: PARP inhibitors as therapeutics: Beyond modulation of PARylation. Cancers (Basel). 12:3942020. View Article : Google Scholar : PubMed/NCBI


Kinoshita T, Nakanishi I, Warizaya M, Iwashita A, Kido Y, Hattori K and Fujii T: Inhibitor-induced structural change of the active site of human poly(ADP-ribose) polymerase. Febs Lett. 556:43–46. 2004. View Article : Google Scholar : PubMed/NCBI


Makhov P, Uzzo RG, Tulin AV and Kolenko VM: Histone-dependent PARP-1 inhibitors: A novel therapeutic modality for the treatment of prostate and renal cancers. Urol Oncol. 39:312–315. 2021. View Article : Google Scholar : PubMed/NCBI


Karpova Y, Guo D, Makhov P, Haines AM, Markov DA, Kolenko V and Tulin AV: Poly(ADP)-Ribosylation Inhibition: A promising approach for clear cell renal cell carcinoma therapy. Cancers (Basel). 13:49732021. View Article : Google Scholar : PubMed/NCBI


Shuch B, Amin A, Armstrong AJ, Eble JN, Ficarra V, Lopez-Beltran A, Martignoni G, Rini BI and Kutikov A: Understanding pathologic variants of renal cell carcinoma: Distilling therapeutic opportunities from biologic complexity. Eur Urol. 67:85–97. 2015. View Article : Google Scholar : PubMed/NCBI


Wang X, Lopez R, Luchtel RA, Hafizi S, Gartrell B and Shenoy N: Immune evasion in renal cell carcinoma: Biology, clinical translation, future directions. Kidney Int. 99:75–85. 2021. View Article : Google Scholar : PubMed/NCBI


Nguyen-Tran HH, Nguyen TN, Chen CY and Hsu T: Endothelial reprogramming stimulated by oncostatin m promotes inflammation and tumorigenesis in VHL-deficient kidney tissue. Cancer Res. 81:5060–5073. 2021. View Article : Google Scholar : PubMed/NCBI


Sharma R, Kadife E, Myers M, Kannourakis G, Prithviraj P and Ahmed N: Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma. J Exp Clin Cancer Res. 40:1862021. View Article : Google Scholar : PubMed/NCBI


Hsieh JJ, Chen D, Wang PI, Marker M, Redzematovic A, Chen YB, Selcuklu SD, Weinhold N, Bouvier N, Huberman KH, et al: Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. Eur Urol. 71:405–414. 2017. View Article : Google Scholar : PubMed/NCBI


Miao D, Margolis CA, Gao W, Voss MH, Li W, Martini DJ, Norton C, Bosse D, Wankowicz SM, Cullen D, et al: Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 359:801–806. 2018. View Article : Google Scholar : PubMed/NCBI


Pal SK, Sonpavde G, Agarwal N, Vogelzang NJ, Srinivas S, Haas NB, Signoretti S, McGregor BA, Jones J, Lanman RB, et al: Evolution of circulating tumor DNA profile from first-line to subsequent therapy in metastatic renal cell carcinoma. Eur Urol. 72:557–564. 2017. View Article : Google Scholar : PubMed/NCBI


Martinez CN, Xie W, Asim BM, Dzimitrowicz H, Burkart J, Geynisman DM, Balakrishnan A, Bowman IA, Jain R, Stadler W, et al: Cabozantinib in advanced non-clear-cell renal cell carcinoma: A multicentre, retrospective, cohort study. Lancet Oncol. 20:581–590. 2019. View Article : Google Scholar : PubMed/NCBI


Maroto P, Anguera G, Roldan-Romero JM, Apellaniz-Ruiz M, Algaba F, Boonman J, Nellist M, Montero-Conde C, Cascon A, Robledo M and Rodríguez-Antona C: Biallelic TSC2 mutations in a patient with chromophobe renal cell carcinoma showing extraordinary response to temsirolimus. J Natl Compr Canc Netw. 16:352–358. 2018. View Article : Google Scholar : PubMed/NCBI


McGregor BA, McKay RR, Braun DA, Werner L, Gray K, Flaifel A, Signoretti S, Hirsch MS, Steinharter JA, Bakouny Z, et al: Results of a multicenter Phase II study of atezolizumab and bevacizumab for patients with metastatic renal cell carcinoma with variant histology and/or sarcomatoid features. J Clin Oncol. 38:63–70. 2020. View Article : Google Scholar : PubMed/NCBI


Fallah J, Brave MH, Weinstock C, Mehta GU, Bradford D, Gittleman H, Bloomquist EW, Charlab R, Hamed SS, Miller CP, et al: FDA approval summary: Belzutifan for von Hippel-Lindau disease associated tumors. Clin Cancer Res. Jun 21–2022.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI


Stransky LA, Vigeant SM, Huang B, West D, Denize T, Walton E, Signoretti S and Kaelin WJ: Sensitivity of VHL mutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway. Proc Natl Acad Sci USA. 119:e21204031192022. View Article : Google Scholar : PubMed/NCBI


He X, Gan F, Zhou Y, Zhang Y, Zhao P, Zhao B, Tang Q, Ye L, Bu J, Mei J, et al: Nonplanar Helicene Benzo[4]Helicenium for the precise treatment of renal cell carcinoma. Small Methods. 5:e21007702021. View Article : Google Scholar : PubMed/NCBI


Yan S, Liu L, Ren F, Gao Q, Xu S, Hou B, Wang Y, Jiang X and Che Y: Sunitinib induces genomic instability of renal carcinoma cells through affecting the interaction of LC3-II and PARP-1. Cell Death Dis. 8:e29882017. View Article : Google Scholar : PubMed/NCBI


Yang XD, Kong FE, Qi L, Lin JX, Yan Q, Loong J, Xi SY, Zhao Y, Zhang Y, Yuan YF, et al: PARP inhibitor Olaparib overcomes Sorafenib resistance through reshaping the pluripotent transcriptome in hepatocellular carcinoma. Mol Cancer. 20:202021. View Article : Google Scholar : PubMed/NCBI


Pletcher JP, Bhattacharjee S, Doan JP, Wynn R, Sindhwani P, Nadiminty N and Petros FG: The Emerging role of poly (ADP-Ribose) polymerase inhibitors as effective therapeutic agents in renal cell carcinoma. Front Oncol. 11:6814412021. View Article : Google Scholar : PubMed/NCBI


Scanlon SE, Hegan DC, Sulkowski PL and Glazer PM: Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient human renal cell carcinoma. Oncotarget. 9:4647–4660. 2018. View Article : Google Scholar : PubMed/NCBI


Zhang Q, Xu Y, Zhang Z, Li J, Xia Q and Chen Y: Folliculin deficient renal cancer cells exhibit BRCA1 a complex expression impairment and sensitivity to PARP1 inhibitor olaparib. Gene. 769:1452432021. View Article : Google Scholar : PubMed/NCBI


Szanto M and Bai P: The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism. Genes Dev. 34:321–340. 2020. View Article : Google Scholar : PubMed/NCBI


Szanto M, Gupte R, Kraus WL, Pacher P and Bai P: PARPs in lipid metabolism and related diseases. Prog Lipid Res. 84:1011172021. View Article : Google Scholar : PubMed/NCBI


Zou Y, Palte MJ, Deik AA, Li H, Eaton JK, Wang W, Tseng YY, Deasy R, Kost-Alimova M, Dancik V, et al: A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun. 10:16172019. View Article : Google Scholar : PubMed/NCBI


Okazaki A, Gameiro PA, Christodoulou D, Laviollette L, Schneider M, Chaves F, Stemmer-Rachamimov A, Yazinski SA, Lee R, Stephanopoulos G, et al: Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers. J Clin Invest. 127:1631–1645. 2017. View Article : Google Scholar : PubMed/NCBI


Shen YA, Hong J, Asaka R, Asaka S, Hsu FC, Suryo RY, Jung JG, Chen YW, Yen TT, Tomaszewski A, et al: Inhibition of the MYC-Regulated glutaminase metabolic axis is an effective synthetic lethal approach for treating chemoresistant ovarian cancers. Cancer Res. 80:4514–4526. 2020. View Article : Google Scholar : PubMed/NCBI


Zhao S, Li P, Wu W, Wang Q, Qian B, Li X and Shen M: Roles of ferroptosis in urologic malignancies. Cancer Cell Int. 21:6762021. View Article : Google Scholar : PubMed/NCBI


Courtney KD, Bezwada D, Mashimo T, Pichumani K, Vemireddy V, Funk AM, Wimberly J, McNeil SS, Kapur P, Lotan Y, et al: Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo. Cell Metab. 28:793–800. 2018. View Article : Google Scholar : PubMed/NCBI


Zhang Y, Huang J, Huang Y, Zhang S and Wu W, Long H, Duan X, Lai Y and Wu W: Tanshinone I and simvastatin inhibit melanoma tumour cell growth by regulating poly (ADP ribose) polymerase 1 expression. Mol Med Rep. 23:402021.PubMed/NCBI


Yun EJ, Lin CJ, Dang A, Hernandez E, Guo J, Chen WM, Allison J, Kim N, Kapur P, Brugarolas J, et al: Downregulation of human DAB2IP gene expression in renal cell carcinoma results in resistance to ionizing radiation. Clin Cancer Res. 25:4542–4551. 2019. View Article : Google Scholar : PubMed/NCBI


Zhou C, Fabbrizi MR, Hughes JR, Grundy GJ and Parsons JL: Effectiveness of PARP inhibition in enhancing the radiosensitivity of 3D spheroids of head and neck squamous cell carcinoma. Front Oncol. 12:9403772022. View Article : Google Scholar : PubMed/NCBI


Meng Y, Efimova EV, Hamzeh KW, Darga TE, Mauceri HJ, Fu YX, Kron SJ and Weichselbaum RR: Radiation-inducible immunotherapy for cancer: Senescent tumor cells as a cancer vaccine. Mol Ther. 20:1046–1055. 2012. View Article : Google Scholar : PubMed/NCBI


Liu Q, Xiao Q, Sun Z, Wang B, Wang L, Wang N, Wang K, Song C and Yang Q: Exosome component 1 cleaves single-stranded DNA and sensitizes human kidney renal clear cell carcinoma cells to poly(ADP-ribose) polymerase inhibitor. Elife. 10:e694542021. View Article : Google Scholar : PubMed/NCBI


Cella D, Motzer RJ, Suarez C, Blum SI, Ejzykowicz F, Hamilton M, Wallace JF, Simsek B, Zhang J, Ivanescu C, et al: Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: An open-label, randomised, phase 3 trial. Lancet Oncol. 23:292–303. 2022. View Article : Google Scholar : PubMed/NCBI


Hagiwara M, Fushimi A, Matsumoto K and Oya M: The Significance of PARP1 as a biomarker for predicting the response to PD-L1 blockade in patients with PBRM1-mutated clear cell renal cell carcinoma. Eur Urol. 81:145–148. 2022. View Article : Google Scholar : PubMed/NCBI


Chabanon RM, Morel D, Eychenne T, Colmet-Daage L, Bajrami I, Dorvault N, Garrido M, Meisenberg C, Lamb A, Ngo C, et al: PBRM1 deficiency confers synthetic lethality to DNA repair inhibitors in cancer. Cancer Res. 81:2888–2902. 2021. View Article : Google Scholar : PubMed/NCBI


Park JS, Lee ME, Jang WS, Rha KH, Lee SH, Lee J and Ham WS: The DEAD/DEAH box helicase, DDX11, is essential for the survival of advanced clear cell renal cell carcinoma and is a determinant of PARP inhibitor sensitivity. Cancers (Basel). 13:25742021. View Article : Google Scholar : PubMed/NCBI


Pan XW, Zhang H, Xu D, Chen JX, Chen WJ, Gan SS, Qu FJ, Chu CM, Cao JW, Fan YH, et al: Identification of a novel cancer stem cell subpopulation that promotes progression of human fatal renal cell carcinoma by single-cell RNA-seq analysis. Int J Biol Sci. 16:3149–3162. 2020. View Article : Google Scholar : PubMed/NCBI


Olson D, Bhalla S, Yang X, Martone B and Kuzel TM: Novel use of targeted therapy via PARP-Inhibition in a rare form of papillary renal cell carcinoma: A case report and literature review. Clin Genitourin Cancer. 14:e445–e448. 2016. View Article : Google Scholar : PubMed/NCBI


Lian BJ, Zhang K, Fang XD, Li F, Dai Z, Chen WY and Qi XP: Clinical benefit of Niraparib to TKI/mTORi-resistance metastatic ccRCC with BAP1-frame shift mutation: Case report and literature review. Front Oncol. 12:9272502022. View Article : Google Scholar : PubMed/NCBI


Saatchi F and Kirchmaier AL: Tolerance of DNA replication stress is promoted by fumarate through modulation of histone demethylation and enhancement of replicative intermediate processing in saccharomyces cerevisiae. Genetics. 212:631–654. 2019. View Article : Google Scholar : PubMed/NCBI


Johnson TI, Costa A, Ferguson AN and Frezza C: Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation. Cell Death Dis. 9:9132018. View Article : Google Scholar : PubMed/NCBI


Sulkowski PL, Sundaram RK, Oeck S, Corso CD, Liu Y, Noorbakhsh S, Niger M, Boeke M, Ueno D, Kalathil AN, et al: Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat Genet. 50:1086–1092. 2018. View Article : Google Scholar : PubMed/NCBI


Sulkowski PL, Oeck S, Dow J, Economos NG, Mirfakhraie L, Liu Y, Noronha K, Bao X, Li J, Shuch BM, et al: Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature. 582:586–591. 2020. View Article : Google Scholar : PubMed/NCBI


Ueno D, Vasquez JC, Sule A, Liang J, van Doorn J, Sundaram R, Friedman S, Caliliw R, Ohtake S, Bao X, et al: Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-ribose polymerase inhibitors and low-dose alkylating chemotherapy. Oncotarget. 13:1054–1067. 2022. View Article : Google Scholar : PubMed/NCBI


Li X, Hu D, Li Y, Luo Y, Liang B, Yu K, Xiong W and Zuo D: Overexpression of TP53INP2 promotes apoptosis in clear cell renal cell cancer via caspase-8/TRAF6 signaling pathway. J Immunol Res. 2022:12604232022.PubMed/NCBI


Lee HK, Cha HS, Nam MJ, Park K, Yang YH, Lee J and Park SH: Broussochalcone A induces apoptosis in human renal cancer cells via ROS level elevation and activation of FOXO3 signaling pathway. Oxid Med Cell Longev. 2021:28007062021. View Article : Google Scholar : PubMed/NCBI


Xu X, Chua CC, Zhang M, Geng D, Liu CF, Hamdy RC and Chua BH: The role of PARP activation in glutamate-induced necroptosis in HT-22 cells. Brain Res. 1343:206–212. 2010. View Article : Google Scholar : PubMed/NCBI


Zheng W, Zhou CY, Zhu XQ, Wang XJ, Li ZY, Chen XC, Chen F, Che XY and Xie X: Oridonin enhances the cytotoxicity of 5-FU in renal carcinoma cells by inducting necroptotic death. Biomed Pharmacother. 106:175–182. 2018. View Article : Google Scholar : PubMed/NCBI


Tsai MF, Chen SM, Ong AZ, Chung YH, Chen PN, Hsieh YH, Kang YT and Hsu LS: Shikonin induced program cell death through generation of reactive oxygen species in renal cancer cells. Antioxidants (Basel). 10:18312021. View Article : Google Scholar : PubMed/NCBI


Clou E and Luque Y: Angiogenesis inhibitors: Mechanism of action and nephrotoxicity. Nephrol Ther. 18:1–6. 2022.(In French). View Article : Google Scholar : PubMed/NCBI


Al-Harbi NO, Imam F, Alharbi MM, Khan MR, Qamar W, Afzal M, Algahtani M, Alobaid S, Alfardan AS, Alshammari A, et al: Role of rivaroxaban in sunitinib-induced renal injuries via inhibition of oxidative stress-induced apoptosis and inflammation through the tissue nacrosis factor-α induced nuclear factor-κappa B signaling pathway in rats. J Thromb Thrombolysis. 50:361–370. 2020. View Article : Google Scholar : PubMed/NCBI


Studentova H, Volakova J, Spisarova M, Zemankova A, Aiglova K, Szotkowski T and Melichar B: Severe tyrosine-kinase inhibitor induced liver injury in metastatic renal cell carcinoma patients: Two case reports assessed for causality using the updated RUCAM and review of the literature. BMC Gastroenterol. 22:492022. View Article : Google Scholar : PubMed/NCBI


Wang Y, An R, Umanah GK, Park H, Nambiar K, Eacker SM, Kim B, Bao L, Harraz MM, Chang C, et al: A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1. Science. 354:aad68722016. View Article : Google Scholar : PubMed/NCBI


Santos SS, Brunialti M, Soriano FG, Szabo C and Salomao R: Repurposing of clinically approved Poly-(ADP-Ribose) polymerase inhibitors for the therapy of sepsis. Shock. 56:901–909. 2021. View Article : Google Scholar : PubMed/NCBI


Mukhopadhyay P, Horvath B, Kechrid M, Tanchian G, Rajesh M, Naura AS, Boulares AH and Pacher P: Poly(ADP-ribose) polymerase-1 is a key mediator of cisplatin-induced kidney inflammation and injury. Free Radic Biol Med. 51:1774–1788. 2011. View Article : Google Scholar : PubMed/NCBI


Jang HR, Lee K, Jeon J, Kim JR, Lee JE, Kwon GY, Kim YG, Kim DJ, Ko JW and Huh W: Poly (ADP-Ribose) polymerase inhibitor treatment as a novel therapy attenuating renal ischemia-reperfusion injury. Front Immunol. 11:5642882020. View Article : Google Scholar : PubMed/NCBI


Ahmad A, Olah G, Herndon DN and Szabo C: The clinically used PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in a murine model of third-degree burn injury. Br J Pharmacol. 175:232–245. 2018. View Article : Google Scholar : PubMed/NCBI


Onji H and Murai J: Reconsidering the mechanisms of action of PARP inhibitors based on clinical outcomes. Cancer Sci. 113:2943–2951. 2022. View Article : Google Scholar : PubMed/NCBI


Simonaggio A, Epaillard N, Elaidi R, Sun CM, Moreira M, Oudard S and Vano YA: Impact of molecular signatures on the choice of systemic treatment for metastatic kidney cancer. Bull Cancer. 107 (Suppl):S24–S34. 2020.(In French). View Article : Google Scholar : PubMed/NCBI


Konstantinopoulos PA, Barry WT, Birrer M, Westin SN, Cadoo KA, Shapiro GI, Mayer EL, O'Cearbhaill RE, Coleman RL, Kochupurakkal B, et al: Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: A dose-escalation and dose-expansion phase 1b trial. Lancet Oncol. 20:570–580. 2019. View Article : Google Scholar : PubMed/NCBI


Abbotts R, Dellomo AJ and Rassool FV: Pharmacologic induction of BRCAness in BRCA-proficient cancers: Expanding PARP inhibitor use. Cancers (Basel). 14:26402022. View Article : Google Scholar : PubMed/NCBI


Nelson LJ, Castro KE, Xu B, Li J, Dinh NB, Thompson JM, Woytash J, Kipp KR and Razorenova OV: Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma. Cell Cycle. 21:1103–1119. 2022. View Article : Google Scholar : PubMed/NCBI


Zhao Y, Zhou K, Xia X, Guo Y and Tao L: Chk1 inhibition-induced BRCAness synergizes with olaparib in p53-deficient cancer cells. Cell Cycle. 1–13. 2022.doi: 10.1080/15384101.2022.2111769 (Epub ahead of print). View Article : Google Scholar


Zhou J, Gelot C, Pantelidou C, Li A, Yucel H, Davis RE, Farkkila A, Kochupurakkal B, Syed A, Shapiro GI, et al: A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nat Cancer. 2:598–610. 2021. View Article : Google Scholar : PubMed/NCBI


Ding L, Chen X, Xu X, Qian Y, Liang G, Yao F, Yao Z, Wu H, Zhang J, He Q and Yang B: PARP1 suppresses the transcription of PD-L1 by Poly(ADP-Ribosyl)ating STAT3. Cancer Immunol Res. 7:136–149. 2019. View Article : Google Scholar : PubMed/NCBI


Jiao S, Xia W, Yamaguchi H, Wei Y, Chen MK, Hsu JM, Hsu JL, Yu WH, Du Y, Lee HH, et al: PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res. 23:3711–3720. 2017. View Article : Google Scholar : PubMed/NCBI


Higuchi T, Flies DB, Marjon NA, Mantia-Smaldone G, Ronner L, Gimotty PA and Adams SF: CTLA-4 blockade synergizes therapeutically with PARP inhibition in BRCA1-deficient ovarian cancer. Cancer Immunol Res. 3:1257–1268. 2015. View Article : Google Scholar : PubMed/NCBI


Gallo D, Young JTF, Fourtounis J, Martino G, Alvarez-Quilon A, Bernier C, Duffy NM, Papp R, Roulston A, Stocco R, et al: CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Nature. 604:749–756. 2022. View Article : Google Scholar : PubMed/NCBI


Bajrami I, Marlow R, van de Ven M, Brough R, Pemberton HN, Frankum J, Song F, Rafiq R, Konde A, Krastev DB, et al: E-Cadherin/ROS1 inhibitor synthetic lethality in breast cancer. Cancer Discov. 8:498–515. 2018. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

Volume 48 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
Spandidos Publications style
Lai Y, Li Z, Lu Z, Zheng H, Chen C, Liu C, Yang Y, Tang F and He Z: Roles of DNA damage repair and precise targeted therapy in renal cancer (Review). Oncol Rep 48: 213, 2022
Lai, Y., Li, Z., Lu, Z., Zheng, H., Chen, C., Liu, C. ... He, Z. (2022). Roles of DNA damage repair and precise targeted therapy in renal cancer (Review). Oncology Reports, 48, 213.
Lai, Y., Li, Z., Lu, Z., Zheng, H., Chen, C., Liu, C., Yang, Y., Tang, F., He, Z."Roles of DNA damage repair and precise targeted therapy in renal cancer (Review)". Oncology Reports 48.6 (2022): 213.
Lai, Y., Li, Z., Lu, Z., Zheng, H., Chen, C., Liu, C., Yang, Y., Tang, F., He, Z."Roles of DNA damage repair and precise targeted therapy in renal cancer (Review)". Oncology Reports 48, no. 6 (2022): 213.