Current data suggests that ACC occurs more frequently in females, with a distribution of 60% in females compared with 40% in males (15). The overall incidence of ACC accounts for ~4.5 cases per 100,000 individuals (16), representing ~1% of all types of head and neck cancer and ~10% of all salivary gland tumors (17). ACC, originating from the mucous glands, can occur in various body sites beyond the salivary glands (18). A large proportion of the available literature indicates that minor salivary glands represent the most common site for ACC, accounting for >50% of cases. The palate is the most frequently affected location, although ACC can also develop in the tongue, paranasal sinuses, nasopharynx, larynx and lacrimal glands (19,20). Among the major salivary glands, the parotid gland is the most prevalent site for ACC (21). Additionally, ACC may arise in the breast, tracheobronchial tree, lungs, prostate, esophagus, skin, Bartholin glands and cervix (22). Although this malignancy can occur at any age, it is most commonly diagnosed in patients between 50 and 60 years of age (23).

Due to the rarity of ACC, the precise etiology and pathogenesis remain poorly understood (24). While smoking and alcohol intake are known risk factors for other types of cancer in the head and neck area, especially squamous cell carcinoma, they have not been confirmed as risk factors for ACC (25). Several genetic and chromosomal alterations, including TP53, NOTCH1, NOTCH2 or loss of the CDKN2A/CDKN2B locus, may be involved in ACC pathogenesis, with a recurrent t(6;9)(q23;p23) translocation resulting in a fusion between the MYB proto-oncogene, transcription factor (MYB) and nuclear factor I/B (NFIB) genes, considered to be a genetic hallmark of ACC (26). Nonetheless, the exact causes of ACC, including potential risk factors, require additional research.

The symptoms of ACC can vary depending on the location of the tumor (27), with a lack of symptoms reported if the tumor is located in the paranasal sinuses or dysphagia if it is located on the hard palate, the base of the tongue or the throat mucosa (28). Dyspnea, coughing, hoarseness or wheezing may occur if the minor salivary glands of the upper aerodigestive tract are involved (29). In advanced stages of the disease, dull pain and altered sensation of the tongue, palate or face may occur, which are manifestations of perineural invasion (PNI) of the local nerves, a characteristic phenomenon of ACC (30). PNI is relatively common, affecting ~43.2% of cases and is considered an independent factor for a poor prognosis (31). Despite its slow development, ACC is considered an aggressive tumor that can readily invade the surrounding tissues. Other factors that can influence the risk of distant metastases include a solid histology, a tumor size >3 cm and the involvement of loco-regional lymph nodes (32). Distant metastases are not uncommon and tend to spread via the perivascular route, typically affecting the lungs, followed by the bones and liver (33). As a result, local recurrences (60%) and distant metastases (40%) are frequent, and can occur even decades after definitive treatment (34). The 5-year overall survival rate ranges from 55 to 70%, which is higher compared with that of other sinonasal malignancies, but the overall survival rate drops to 40% at 10 years and further to 15% at 20 years after diagnosis. Therefore, extended follow-up for at least 15 years, if not lifelong follow-up, is necessary (35). Distinguishing salivary ACC from other malignant salivary tumors requires advanced pathological skills. ACC shares histopathological features with other salivary gland tumors, such as polymorphous adenocarcinoma and basal cell adenocarcinoma (27). The cribriform, tubular and solid growth patterns observed in ACC can occasionally resemble other malignancies, including pleomorphic adenoma or polymorphous low-grade adenocarcinoma, leading to diagnostic confusion (36). While the classic cribriform pattern is often recognizable, the tubular and solid variants can be more difficult to distinguish from other salivary gland tumors, particularly when these patterns dominate the tumor (36). Therefore, the role of expert pathological review in the diagnosis of salivary ACC is crucial due to the propensity of the tumor for late local recurrence and distant metastasis. In such cases, experienced pathologists could accurately evaluate biopsy samples to confirm the presence of recurrent or metastatic ACC and distinguish it from other possible malignancies or benign conditions. Expert pathological review would serve as a quality assurance measure, and provide a second opinion to confirm initial diagnoses and prevent diagnostic errors. The role of molecular diagnostics in salivary ACC diagnosis is also critical for distinguishing the tumor from other salivary gland tumors. Specifically, the MYB-NFIB gene fusion, a molecular hallmark of ACC, aids in differentiating it from other tumors, such as Warthin's tumor (37). Additionally, while immunohistochemical staining can assist in the diagnosis, markers such as S-100, CK-7, CK-17 or SOX10 are not entirely specific to ACC and may overlap with those of other salivary gland tumors. Therefore, careful interpretation of staining patterns in conjunction with histological findings, is essential. The definitive diagnosis of salivary ACC remains challenging due to the histological diversity of types of salivary gland cancer. This complexity is underscored by the 2022 World Health Organization classification of salivary gland tumors, which introduces new malignant entities such as microsecretory carcinoma and sclerosing microcystic adenocarcinoma (38).

Current treatment options for ACC typically involve surgical resection followed by postoperative radiotherapy, which appears to be a feasible approach for achieving locoregional control in early stage disease (39). In a study by Ishida et al (40), which involved 58 cases of ACC treated solely with surgical excision, the 10-, 20- and 25-year survival rates were 63.7, 27.3 and 20%, respectively. Although surgery remains the preferred therapeutic option for patients with ACC, it often presents significant challenges due to the tumor's location, particularly when it arises from the minor salivary glands in areas such as the paranasal sinuses. Radical resection can be difficult to achieve, which underscores the need for postoperative radiotherapy to compensate for incomplete tumor removal (41). It was previously reported that patients with ACC who did not receive postoperative radiotherapy were >13 times more likely to experience local recurrence (42). Nevertheless, radiotherapy alone is seldom used and is usually dedicated for patients with advanced or recurrent disease (Fig. 1) (43). The frequent incidence of local recurrence and distant metastasis, even years after completion of treatment, highlights the ineffectiveness of these therapies. Furthermore, neither the National Comprehensive Cancer Network (NCCN) (8) nor the American Society of Clinical Oncology (44) provides specific guidelines for effective chemotherapeutic regimens in the management of ACC. In palliative cases, chemotherapeutic regimens typically include cisplatin and 5-fluorouracil, or combination therapies such as cisplatin, doxorubicin and cyclophosphamide (CAP) (45). However, in the use of monotherapy, agents such as cisplatin, mitoxantrone, epirubicin, vinorelbine, paclitaxel and gemcitabine may be employed (46). Nevertheless, the effectiveness of these chemotherapeutics remains limited, since these drugs are reported to have no or only slight effects on the prognosis of the patient (46). According to data from the available literature, the response rate for CAP is estimated to be between 18 and 31% (47). In a phase II study involving cisplatin and docetaxel, which predominantly included patients with ACC, as well as other types of salivary gland cancer, the median duration of response was 6.8 months. The median progression-free survival time was 9.4 months and the overall survival time was ~28.2 months (48). Nevertheless, the data confirmed that chemotherapy has limited effectiveness in treating ACC and is primarily used as a palliative approach.

Currently, there is no effective systemic therapy for managing ACC of the salivary glands, particularly in advanced stages or for inoperable tumors. This emphasizes the need to explore new treatment strategies, especially those incorporating targeted therapies, to improve the management of late-stage ACC. Although no new systemic therapies for managing ACC have recently been approved, the primary goal of this review is to outline the current therapeutic targets and describe ongoing clinical trials (Table I) that are exploring potential treatment options for ACC, while also providing data on concluded clinical trials (Table II).

An extensive literature search was conducted using the PubMed and Cochrane Library databases. The search strategy utilized combined Medical Subject Headings terms and key words, including: ‘adenoid cystic carcinoma of a salivary gland’ or ‘ACC’, ‘salivary adenoid cystic carcinoma’, and ‘SACC’. There were no restrictions on language, geographical region, patient age or follow-up duration. Prospective or retrospective clinical and animal studies were included in the present review. The exclusion criteria were as follows: Editorials, letters, reviews, case reports, lack of relevant outcome reporting and duplicate publications.

The high expression of VEGF in over two-thirds of patients with ACC has been identified as a potentially promising therapeutic target (49). Molecular studies on ACC have also shown that high MYB expression levels are correlated with increased VEGF expression levels (50–52). Despite this correlation, preclinical studies using the VEGF inhibitor regorafenib, which showed successful results by inhibiting ACC cell migration and intravascular cancer migration, did not translate into clinical benefit for patients with ACC in human trials (53). Similar unsuccessful outcomes were observed in studies assessing the effectiveness of sunitinib or nintedanib in patients with ACC (54,55). However, lenvatinib and axitinib showed relatively higher objective response rates, with 11–16 and 9–17%, respectively (56). In a phase II clinical trial with axitinib and avelumab in patients with recurrent disease, the partial response was confirmed in 28 out of 40 enrolled patients, with a median overall survival time estimated at 16.6 months. However, the aforementioned study reached its primary end point with 4 partial responses in 28 evaluable patients (57,58). Another study conducted on lenvatinib use among patients with recurrent or metastatic ACC demonstrated a partial response in 5 patients only among the 33 enrolled and 32 evaluable for the primary endpoint. A large proportion of patients (24) had stable disease; however, the severe side effects, including hypertension or oral pain, resulted in treatment discontinuation (59). Locati et al (60) evaluated lenvatinib in patients with recurrent or metastatic ACC and found only three partial responses among 26 participants, with a median overall survival time of 27 months, a median progression-free survival time of 9.1 months and a median duration of response of 3.1 months. In another study assessing the impact of VEGFR2 inhibition in recurrent or metastatic ACC, rivoceranib demonstrated limited effectiveness in 72 evaluated patients, with an overall response rate of 15.3%, a median duration of response of 14.9 months and a median progression-free survival time of 9.0 months (61). A clinical trial evaluating the effectiveness of cabozantinib among patients with salivary gland cancer, including ACC, reported high levels of toxicity and was closed prematurely (59). Additionally, in another study, only 1 out of 15 patients with ACC achieved a partial response, which was comparable to the response rates observed in other types of salivary gland cancer (62). Thus, even though VEGFR is highly expressed in ACC tissue, it does not appear to be an effective therapeutic target.

EGFR has been found to be overexpressed in >85% of ACC cases (63). However, therapies targeting EGFR inhibition have shown limited effectiveness in managing ACC. The EGFR monoclonal antibodies act by inhibition of phosphorylation and cellular signaling, and support tumor clearance through antibody-dependent cellular cytotoxicity (ADCC) (64). Previous studies on cetuximab, gefitinib and lapatinib inhibiting both EGFR and HER2 did not change the disease course substantially in patients with ACC (15,65). In a study by Bossi et al (66), cetuximab contributed to disease stabilization for >6 months. Despite the increased expression levels of EGFR in ACC, studies investigating EGFR inhibition have shown no objective responses (67–69). Nevertheless, in a study conducted by Chew et al (70), the co-administration of prochlorperazine (PCZ) with an EGFR inhibitor was investigated as a way to enhance the availability of surface EGFR for antibody binding, thereby improving ADCC. The inhibition of dynamin by PCZ and clathrin-mediated endocytosis allows for increased EGFR expression on the surface of cancer cells, potentially leading to enhanced ADCC and an improved response in patients with recurrent or metastatic ACC (71).

The increased expression of FGFR1 in ACC contributed to research on the potential FGFR1 inhibitors, which may decrease cancer cell proliferation (72). In an experimental animal model of ACC, use of dovitinib, a multi-kinase inhibitor, resulted in slowed disease progression (73). These findings were subsequently validated in a study on dovitinib in patients with ACC conducted by Dillon et al (74), which observed a partial response in 2 patients and disease stabilization in 65% of included patients (71). Despite achieving disease stabilization, 67% of the patients eventually experienced cancer progression, with an overall median progression-free survival of 8.5 months. However, given that dovitinib does not act as a selective kinase inhibitor, it remains unclear whether the observed response in the patients was due to FGFR1 inhibition or other targeted kinases, including KIT, PDGFR, RET, CSF1-R, TrkA and FLT3. An alternative agent, lenvatinib, that inhibits not only FGFR 1–3, but also VEGFR2, KIT proto-oncogene receptor tyrosine kinase (c-KIT), ret proto-oncogene (RET) and platelet EGFRa and b, is considered a more potent therapeutic option (71). A study by Tchekmedyian et al (59) investigating lenvatinib use confirmed a partial response in 32 patients with recurrent or metastatic ACC, with 8 patients showing >20% reduction in tumor size. Both studies on lenvatinib and dovitinib required dosage modifications due to adverse effects such as hypertension, anemia or diarrhea (59,71). Lenvatinib has received a category 2B recommendation for patients with progressive, recurrent or metastatic ACC in the NCCN guidelines (8). A clinical trial combining lenvatinib and pembrolizumab did not show an improved overall response rate compared with lenvatinib alone in patients with ACC. A complete response rate was found in only 1 out of 17 patients, with 13 patients achieving stable disease (75). Another study evaluating the effectiveness of the FGFR1 inhibitor AZD4547 in treating ACC of the lacrimal gland found that adding cisplatin led to lower cell proliferation and migration compared with the control group treated with cisplatin alone (76).

Although receptor tyrosine kinase c-KIT is upregulated in 65–90% of ACC tumors (77), clinical trials involving imatinib, a c-KIT inhibitor, demonstrated that the drug was largely ineffective in treating salivary gland ACC (78). While imatinib has been successful in treating gastrointestinal stromal tumors and chronic myeloid leukemia (79), in one study examining its use in ACC, only 2 out of 42 patients experienced an objective tumor response (80). Similarly, dasatinib failed to show any improvement in patients with recurrent or metastatic ACC (81). Furthermore, the combination of cisplatin with imatinib did not result in any significant improvement in response rates, as only 3 patients (10%) exhibited a partial response (82). Thus, despite the high expression of c-KIT in salivary gland ACC, the protein does not appear to play a significant role in the pathogenesis of this tumor type, rendering it an unattractive target for future therapeutic interventions.

The translocation t(6;9)(q22-23;p23-24), which leads to the fusion of the MYB proto-oncogene with the NFIB transcription factor gene, is a hallmark of ACC, as it is detected in ~50% of cases (83). However, the precise frequency of MYB-NFIB fusions in ACC remains unknown, as it varies depending on the method of detection used (for example, fluorescence in situ hybridization vs. PCR/RNA-seq) and the type of material analyzed (for example, fresh-frozen vs. formalin-fixed paraffin-embedded tissue) (84). MYB protein expression by IHC was recently demonstrated in >90% of ACCs in a large multi-institutional study (85). Moreover, MYB gene upregulation itself serves a key role in the cancer pathogenesis, as it promotes tumorigenesis by enhancing cancer stemness; however, MYB was previously thought to present a difficult therapeutic target due to its nature as a transcription factor (86). Nevertheless, the current and past studies proved that MYB inhibition has had a beneficial effect on patients with ACC. The approach to MYB inhibition may be accomplished by direct MYC degradation or by the inhibition of MYB-associated proteins (87). A study by Yusenko et al (88) confirmed that use of polyether ionophore monensin A results in the inhibition of MYB and leads to its degradation in vitro. All-trans retinoic acid (ATRA) also has an inhibitory effect on the MYB gene in ACC cells (89). Another molecule inhibiting MYB-NFIB fusion is insulin-like growth factor receptor 1 (IGFR1) (90). IGFR1, similar to EGFR, stimulates ACC proliferation as the MYB-NFIB fusion in ACC is regulated by IGF1R through an autocrine loop (90). In ACC models, linstinib targeting IGFR1, crizotinib targeting ALK or geftinib targeting EGFR resulted in tumor growth reduction (91). In a clinical trial evaluating figitumab combined with dacomitinib, and another trial assessing R1507 with sorafenib, the response rate was observed in 1 patient, while stable disease was seen in 3 patients (92,93). However, due to the development of MYB-targeted inhibitors, MYB is becoming an increasingly attractive therapeutic target. In a study conducted by Yusenko et al (94), a Bcr-TMP MYB-inhibitory particle resulted in significantly decreased ACC cell proliferation.

The NOTCH signaling pathway serves a pivotal role in numerous cellular processes that are crucial for cell differentiation, but it has also been implicated in the pathogenesis of several types of cancer, including ACC (95). Although NOTCH1 mutations are less common compared with MYB gene alterations, they are typically found in ~15% of ACC cases (96). Furthermore, studies suggest that NOTCH mutations in patients with ACC are associated with a poorer prognosis (97). Given the role of NOTCH signaling in regulating tumor cell behavior, acting as both an oncogene and a tumor suppressor depending on the cellular and tissue context, NOTCH inhibitors are an appealing therapeutic strategy for certain subsets of ACC. Several preclinical studies have confirmed the effectiveness of NOTCH1 inhibitors in ACC patient-derived xenograft (PDX) models (98). A previous study examined AL101 (osugacestat), a potent γ-secretase inhibitor that prevents the activation of all four NOTCH receptors (99). The antitumor activity of AL101 was demonstrated in ACC cell lines, organoids and PDX models (99). Notably, AL101 showed strong antitumor effects in both in vitro and in vivo models of ACC with activating NOTCH1 mutations that constitutively upregulated NOTCH signaling pathways (99). This provides a rationale for further clinical trials evaluating AL101 in patients with NOTCH-driven relapsed or refractory ACC. In a phase II clinical trial assessing AL101, 9 out of 77 patients experienced a partial response, while 44 had stable disease (99). In a phase I study of the pan-NOTCH inhibitor CB-103 for patients with ACC and other tumors, no partial response was observed, but 23 out of 40 patients with ACC had stable disease, with a median progression-free survival time of 2.5 months and a median overall survival yime of 18.4 months (100). A study of crenigacestat another pan-NOTCH inhibitor, demonstrated that only 1 out of 22 patients with ACC had a partial response, while 15 experienced stable disease (101). Another trial testing brontictuzumab targeting Notch1 receptor, showed favorable effects, with 2 out of 12 patients achieving a partial response and 3 achieving stable disease (102).

Although p53 can be considered one of the most notable genes with mutations commonly found in numerous types of cancer, its incidence in ACC is less common, accounting for 10–20% of cases (103). However, in a previous study, increased p53 expression was observed in ~90% of ACC cases, indicating that it might serve as a potential therapeutic target (104). In the ACC PDX model, inhibiting the interaction between murine double minute 2 (MDM2) and p53 using MI-733 led to apoptosis, tumor regression and the prevention of tumor recurrence (105). Following this, a clinical trial is currently underway, assessing the efficacy of blocking MDM2-p53 with alrizomadlin (APG-115), with or without platinum-based therapy, in salivary gland cancer, including ACC, with results yet to be published (106).

PI3K activates AKT by phosphorylation and via certain transcriptional factors, including mTOR (107). In a study by Yu et al (108), proteins such as p-S6, p-STAT3, PAI, EGFR and hypoxia induced factor-1α were significantly elevated in ACC samples compared with those in benign salivary lesions, such as pleomorphic adenoma and normal salivary glands. Similarly, a study by Liu et al (109) demonstrated decreased expression levels of PTEN in ACC samples, particularly in the solid subtype, compared with other salivary gland malignancies. Given that PTEN functions as a tumor suppressor, its reduced expression levels in ACC tissue might present a potential therapeutic target. In a phase II clinical trial involving everolimus, an mTOR inhibitor, among patients with ACC showing disease progression, treatment with everolimus resulted in a median progression-free survival time of 11.2 months. Of the 34 participants included, 15 showed tumor shrinkage and 27 exhibited stable disease (110). Additionally, a separate phase I study investigating the combination of everolimus with lenalidomide found that this regimen was safe and well tolerated, indicating a potential combination therapy for ACC (111).

Immunotherapy has transformed the treatment landscape for numerous types of cancer that previously had a poor prognosis. It is now a primary treatment option for several malignancies and is considered to be promising approach in cancer therapy (112–114). The expression levels of proteins such as cytotoxic T cell antigen 4 (CTLA-4), programmed death receptor 1 (PD-1) and programmed death-ligand 1 (PD-L1), which are primary targets for immunotherapeutic treatments, is significantly low in the environment of ACC (115). As ACC is considered to be a ‘cold tumor’, the lymphocytic infiltration in its microenvironment is sparse (116). Therefore, both past and ongoing research on the use of immunotherapy in ACC has yielded unsatisfactory results (15,117). The NISCAHN trial examined the efficacy of nivolumab, a PD-1 inhibitor, in 45 patients with recurrent or metastatic ACC. The results showed an overall response rate of only 0.8%, with a progression-free survival time of 6 months for 33% of patients (118). Another study of ACC patients, where nivolumab was combined with the CTLA-4 inhibitor ipilimumab, reported an even lower overall response rate compared with nivolumab alone, at ~6% (119). Additionally, a study assessing the effects of pembrolizumab acting as an PD1 inhibitor, with or without concomitant radiotherapy, did not demonstrate any significant tumor response (120). A clinical trial of pembrolizumab with or without radiotherapy showed that 65% of patients achieved disease stabilization for an average of 11 months, but no objective responses were recorded. In a study by Mosconi et al (121), no expression of PD-1 or PD-L1 was detected in ACC samples. These findings were corroborated by similar results in a study conducted by Guazzo et al (122). By contrast, the high expression level of PD-L2 in ACC tissue has garnered increasing interest in the research field (123,124). In a clinical trial of ACC patients, the PD-1 antibody BGB-A317, which acts as an inhibitor of both PD-L1 and PD-L2, was combined with the Tet-MYB vaccine (125). It appears that the PD-L1 inhibitors enhance the antitumor effect by restoring T-cell activity and improving the immune system's ability to recognize and attack tumor cells (126).

In the realm of immunomodulatory therapies, the TeTMYB vaccine has been developed to target MYB. This vaccine was constructed using a full-length MYB complementary DNA bound by two potent CD4⁺ epitopes derived from the tetanus toxin, which was subsequently cloned into the complementary DNA vaccine vector pVAX1 (127). Previously, the TeTMYB vaccine demonstrated efficacy in targeting MYB-expressing colorectal cancer in experimental animal studies (127). Subsequently, the TeTMYB vaccine underwent a phase I clinical trial not only for colorectal cancer, but also for salivary gland ACC (125).

The PRMT5 inhibitor, targets PRMT5, an enzyme responsible for the methylation of arginine residues that serves a significant role in various cellular processes, including cell cycle control, DNA repair or signal transduction (128). However, its role has also been linked to the pathogenesis of several types of cancer, including ACC (129). The involvement of PRMT5 in cancer is primarily due to its inhibition of tumor suppressor gene expression, leading to a loss of control over carcinogenesis (130). In a phase I clinical trial involving 14 patients with ACC, the PRMT5 inhibitor GSK3326595 demonstrated a partial response rate of 21% (3 out of 14 patients) (130). Another study evaluating the PRMT inhibitor PRT543 in patients with recurrent or metastatic ACC reported a median progression-free survival time of 5.9 months. With 56 patients participating, the overall response rate was 2% and disease stabilization was observed in 7% of cases (131).

The TRK family, a group of receptor tyrosine kinases encoded by NTRK genes, plays a crucial role in the development and proper functioning of the nervous system. TRKA, along with nerve growth factor, is associated with PNI, a phenomenon highly characteristic of ACC and responsible for late recurrences or distant metastases (132). A phase-I clinical trial is assessing the effectiveness of a small molecule, VMD-928, which acts as a TRKA inhibitor, in solid tumors including ACC; however, the results of this trial are yet to be published (133).

PSMA expression is characteristic not only of prostate cancer cells, but also for other malignant diseases, including salivary ACC (134). Under normal conditions, PSMA may be present on the surface of serous and mucous acinar cells, as well as intercalated and striated duct cells (135). Moreover, PSMA appears to be more densely distributed in the major salivary glands than in the minor salivary glands, as evidenced by the increased uptake of PSMA-ligand on diagnostic images in major salivary glands (136). A study by Klein Nulent et al (135) found that PSMA expression was observed in 94% of primary ACC cases, 80% of recurrent tumors and 90% of metastatic tumors. In ACC, PSMA is predominantly localized on the surface of cancer cells, which has driven research into PSMA-based theranostics (135). A phase II study conducted by van Boxtel et al (137) using 68Ga-PSMA PET demonstrated PSMA ligand uptake in 93% of patients with ACC. These findings led to the initiation of a phase II trial focusing on PSMA radionuclide therapy (138). Given these results, PSMA expression in ACC could serve as a potential diagnostic marker and open new avenues for innovative therapeutic approaches in the future.

AKT serves a pivotal role in various signaling pathways and is often dysregulated in numerous types of human cancer (139). In a study involving patients with advanced stage incurable ACC, the use of MK-2206, an allosteric inhibitor of AKT, yielded no confirmed responses (140). Of the 14 included patients, 13 patients had stable disease, while 1 patient developed disease progression. The median progression-free survival time was 9.7 months, and the median overall survival time was 18.0 months (140). Consequently, AKT inhibition by MK-2206 failed to produce a significant clinical response in patients with ACC. Additionally, in lung cancer, the activation of AKT, which inhibits transcription-dependent mechanisms of ATRA, promotes invasion and cell survival, leading to resistance against retinoic acid treatment (141). This implies that AKT could be a potential therapeutic target not only in lung cancer but also in ACC.

Given the high recurrence rates and chemoresistance of ACC, treatments targeting CSCs, which function as tumor-initiating cells and drive chemoresistance, may hold potential in ACC treatment (142). Although CSCs make up ~5% of all tumor cells, they are responsible for tumor heterogeneity and the capacity for self-renewal, making them a potential target for ACC management (143). Therefore, inhibitors targeting CSCs might lead to tumor regression, typically in combination with cytotoxic therapies aimed at simultaneously reducing tumor mass. Therefore, eliminating CSCs could also help reduce recurrence rates, as these cells drive ongoing tumor renewal (144). In a preclinical PDX model of ACC, inhibiting the interaction of MDM2-p53 with a small molecule inhibitor reduced the number of CSCs and increased sensitivity to cisplatin (145). Moreover, after neoadjuvant administration of MI773 and subsequent tumor resection in a preclinical study, no recurrence was observed compared with the control group that were treated with surgical tumor removal alone (107). A preclinical study on vorinostat, a histone deacetylase inhibitor, also demonstrated a reduction in CSCs in ACC (146). Additionally, the combination of vorinostat with cisplatin showed a decreased number of CSCs, indicating its potential to sensitize ACC cells to cisplatin (147). However, in a clinical trial with vorinostat and patients with recurrent/metastatic ACC, only 2 patients had a partial response, while 27 exhibited stable disease (147). A phase II clinical trial assessing the combination of chidamide and cisplatin is currently ongoing (69). In another study that focused on stemness inhibition assessing amcasertib (BBI503), which acts as multiple serine-threonine kinases inhibitor, the disease control rate was assessed at 86%, with 79% alive in the first year of survival since diagnosis (12).

The expression of CDK6 is significantly elevated in ACC samples, measuring 4-fold higher by mass spectrometry compared with that in squamous cell carcinoma (SCC) samples, and 3-fold higher at the mRNA level (148). Furthermore, the expression of the p16 protein, which inhibits CDK6, was observed to be notably lower in ACC samples compared with that in SCC samples (148). Since cyclins and CDKs are key regulators of the cell cycle, with CDK6 inactivating the retinoblastoma protein that acts as a G₁ phase cell cycle inhibitor (149), these findings suggest that CDK6 may serve a key role in the pathogenesis of ACC and therefore, could be considered as a potential therapeutic target for future investigation.

Chemokines serve important roles in both innate and adaptive immunity (150). CXCR4 is commonly expressed on numerous types of cancer cells, with its ligand, CXCL12, contributing to cancer progression by promoting cell proliferation, migration and metastasis (151). Under normal conditions, CXCL4 is found on the surface of mesenchymal stromal cells in the lungs, liver, lymph nodes, bone marrow and peripheral nerves (152). In a study conducted by Nulent et al (152), CXCR4 expression was observed in 81% of ACC samples. Currently available literature provides data on a number of CXCR4 antagonists, including inhibitors, antibodies and microRNAs, which have been developed to target CXCR4 (153). Nevertheless, CXCR4 antagonists have been found to have limited success in clinical trials due to cellular toxicity, and poor stability and efficacy (153). Moreover, in one study, CXCL12/CXCR4 expression was found to potentially promote PNI by inducing tumor cell differentiation into Schwann-like cells via the Twist/S100A4 axis in salivary ACC (153). However, there are currently no clinical trials assessing the efficacy of these agents in patients with ACC.