Targeting the mitogen‑activated protein kinase kinase and protein kinase A pathways overcomes acquired resistance to Selumetinib in low‑grade glioma cells

Melotti,Linda; Meco,Daniela; Battaglia,Alessandra; Buzzonetti,Alexia; Martini,Maurizio; Ruggiero,Antonio; Scambia,Giovanni; Riccardi,Riccardo

doi:10.3892/or.2020.7867

Targeting the mitogen‑activated protein kinase kinase and protein kinase A pathways overcomes acquired resistance to Selumetinib in low‑grade glioma cells

Authors:
- Linda Melotti
- Daniela Meco
- Alessandra Battaglia
- Alexia Buzzonetti
- Maurizio Martini
- Antonio Ruggiero
- Giovanni Scambia
- Riccardo Riccardi
View Affiliations

Affiliations: Pediatric Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, I‑00168 Rome, Italy, Department of Life Science and Public Health, Catholic University of Sacred Heart, I‑00168 Rome, Italy, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, I‑00168 Rome, Italy, Department of Pathology, Fondazione Policlinico A. Gemelli, Catholic University of the Sacred Heart, I‑00141 Rome, Italy
Published online on: November 25, 2020 https://doi.org/10.3892/or.2020.7867
Pages: 752-763

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

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

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The Ras/Raf/MEK/MAPK signaling cascade is frequently activated in human cancer and serves a crucial role in the oncogenesis of pediatric low‑grade gliomas (PLGGs). Therefore, drugs targeting kinases among the mitogen‑activated protein kinase (MAPK) effectors of receptor tyrosine kinase signaling may represent promising candidates for the treatment of PLGGs. The aim of the present study was to elucidate the anticancer effects of the MEK inhibitor Selumetinib on two low‑grade glioma cell lines and the possible underlying effects on intracellular signal transduction. The two cancer cell lines displayed different levels of sensitivity to Selumetinib, as Res186 cells were resistant (IC50>1 µM), whereas Res259 cells were sensitive (IC50≤1 µM) to MEK inhibition. Despite the different levels of sensitivity, Selumetinib mediated the phosphorylation of AKT and MEK in both cell lines and suppressed the phosphorylated MAPK cascades. In addition, Selumetinib induced cell cycle arrest at the G0/G1 phase by downregulating the expression levels of cyclin D1 and p21 and upregulating those of p27 compared with those in the control cells. A Res259 cell line with acquired resistance to Selumetinib (Res259/R) was next established and biologically and molecularly characterized, and it was demonstrated that addition of a selective cAMP‑dependent protein kinase A inhibitor to Selumetinib overcame drug resistance in Res 259/R cells. In conclusion, the results of the present study provided three low‑grade glioma cell line models characterized by sensitivity, intrinsic and acquired resistance to Selumetinib, which may be usuful tools to study new mechanisms of chemoresistance to MEK inhibitors and to explore alternative therapeutic strategies in low‑grade gliomas for personalization of treatment.

View Figures

View References

1	Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, Wolinsky Y, Kruchko C and Barnholtz-Sloan JS: CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro Oncol. 17 (Suppl 4):iv1–iv62. 2015. View Article : Google Scholar : PubMed/NCBI
2	Johnson KJ, Cullen J, Barnholtz-Sloan JS, Ostrom QT, Langer CE, Turner MC, McKean-Cowdin R, Fisher JL, Lupo PJ, Partap S, et al: Childhood brain tumor epidemiology: A brain tumor epidemiology consortium review. Cancer Epidemiol Biomarkers Prev. 23:2716–2736. 2014. View Article : Google Scholar : PubMed/NCBI
3	Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P and Ellison DW: The 2016 world health organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131:803–82. 2016. View Article : Google Scholar : PubMed/NCBI
4	Sievert AJ and Fisher MJ: Pediatric low-grade gliomas. J Child Neurol. 24:1397–1408. 2009. View Article : Google Scholar : PubMed/NCBI
5	Bergthold G, Bandopadhayay P, Bi WL, Ramkissoon L, Stiles C, Segal RA, Beroukhim R, Ligon KL, Grill J and Kieran MW: Pediatric low-grade gliomas: How modern biology reshapes the clinical field. Biochim Biophys Acta. 1845:294–307. 2014.PubMed/NCBI
6	Chalil A and Ramaswamy V: Low grade gliomas in children. J Child Neurol. 31:517–522. 2016. View Article : Google Scholar : PubMed/NCBI
7	Dasgupta T, Olow AK, Yang X, Hashizume R, Nicolaides TP, Tom M, Aoki Y, Berger MS, Weiss WA, Stalpers LJ, et al: Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma. Neurooncol. 126:385–393. 2016. View Article : Google Scholar
8	Ater Jl, Zhou T, Holmes E, Mazewski CM, Booth TN, Freyer DR, Lazarus KH, Packer RJ, Prados M, Sposto R, et al: Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: A report from the children's oncology group. J Clin Oncol. 30:2641–2647. 2012. View Article : Google Scholar : PubMed/NCBI
9	Bandopadhayay P, Bergthold G, London WB, Goumnerova LC, Morales La Madrid A, Marcus KJ, Guo D, Ullrich NJ, Robison NJ, Chi SN, et al: Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: An analysis of the surveillance epidemiology and end results (SEER) database. Pediatr Blood Cancer. 61:1173–1179. 2014. View Article : Google Scholar : PubMed/NCBI
10	Weuken JW and Wesseling P: MAPK pathway activation through BRAF gene fusion in pilocytic astrocytomas; a novel oncogenic fusion gene with diagnostic, prognostic, and therapeutic potential. J Pathol. 222:324–328. 2010. View Article : Google Scholar : PubMed/NCBI
11	Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y and Hu LL: ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 19:1997–2007. 2019.
12	Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, Toedt G, Wittmann A, Kratz C, Olbrich H, et al: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 118:1739–1749. 2008. View Article : Google Scholar : PubMed/NCBI
13	Tateishi K, Nakamura T and Yamamoto T: Molecular genetics and therapeutic targets of pediatric low-grade gliomas. Brain Tumor Pathol. 36:74–83. 2019. View Article : Google Scholar : PubMed/NCBI
14	Roskoski R Jr: MEK1/2 dual-specificity protein kinases: Structure and regulation. Biochem Biophys Res Commun. 417:5–10. 2012. View Article : Google Scholar : PubMed/NCBI
15	Roskoski R Jr: ERK1/2 MAP kinases: Structure, function, and regulation. Pharmacol Res. 66:105–143. 2012. View Article : Google Scholar : PubMed/NCBI
16	Roskoski R Jr: Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas. Pharmacol Res. 117:20–31. 2017. View Article : Google Scholar : PubMed/NCBI
17	Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, Parry J, Smith D, Brandhuber BJ, Gross S, et al: Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 13:1576–1583. 2007. View Article : Google Scholar : PubMed/NCBI
18	Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, Cockerill M, Cartlidge S and Smith PD: AZD6244 (ARRY- 142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 kinases: Mechanism of action in vivo, pharmacokinetic/pharmacodynamics relationship, and potential for combination in preclinical models. Mol Cancer Ther. 6:2209–2219. 2007. View Article : Google Scholar : PubMed/NCBI
19	Deming DA, Cavalcante LL, Lubner SJ, Mulkerin DL, Conte L, Eickhoff JC, Kolesar JM, Fioravanti S, Greten TF, Compton K, et al: A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer. Invest New Drugs. 34:168–175. 2016. View Article : Google Scholar : PubMed/NCBI
20	Greystoke A, Steele N, Arkenau HT, Blackhall F, Haris N, Lindsay CR, Califano R, Voskoboynik M, Summers Y, So K, et al: SELECT-3: A phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting. Br J Cancer. 117:938–946. 2017. View Article : Google Scholar : PubMed/NCBI
21	Melosky B, Bradbury P, Tu D, Florescu M, Reiman A, Nicholas G, Basappa N, Rothenstein J, Goffin JR, Laurie SA, et al: Selumetinib in patients receiving standard pemetrexed and platinum-based chemotherapy for advanced or metastatic KRAS wildtype or unknown non-squamous non-small cell lung cancer: A randomized, multicenter, phase II study. Canadian cancer trials group (CCTG) IND.219. Lung Cancer. 133:48–55. 2019. View Article : Google Scholar : PubMed/NCBI
22	Torii S, Yamamoto T, Tsuchiya Y and Nishida E: ERK MAP kinase in G cell cycle progression and cancer. Cancer Sci. 97:697–702. 2006. View Article : Google Scholar : PubMed/NCBI
23	Bax DA, Little SE, Gaspar N, Perryman L, Marshall L, Viana-Pereira M, Jones TA, Williams RD, Grigoriadis A, Vassal G, et al: Molecular and phenotypic characterisation of paediatric glioma cell lines as models for preclinical drug development. PLoS One. 4:e52092009. View Article : Google Scholar : PubMed/NCBI
24	Chou TC: Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 15:440–446. 2011.
25	Adjei AA, Cohen RB, Franklin WB, Morris C, Wilson D, Molina JR, Hanson LJ, Gore L, Chow L, Leong S, et al: Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 26:2139–2146. 2008. View Article : Google Scholar : PubMed/NCBI
26	Chen YH and Gutmann DH: The molecular and cell biology of pediatric low-grade gliomas. Oncogene. 33:2019–2026. 2014. View Article : Google Scholar : PubMed/NCBI
27	Khatua S, Gutmann DH and Packer RJ: Neurofibromatosis type 1 and optic pathway glioma: Molecular interplay and therapeutic insights. Pediatr Blood Cancer. 65:2018. View Article : Google Scholar : PubMed/NCBI
28	Yang L, Jackson E, Woerner BM, Perry A, Piwnica-Worms D and Rubin JB: Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. Cancer Res. 67:651–658. 2007. View Article : Google Scholar : PubMed/NCBI
29	Warriton NM, Gianino SM, Jackson E, Goldhoff P, Garbow JR, Piwnica-Worms D, Gutmann DH and Rubin JB: Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1. Cancer Res. 70:5717–5727. 2010. View Article : Google Scholar : PubMed/NCBI
30	Xing F, Luan Y, Cai J, Wu S, Mai J, Gu J, Zhang H, Li K, Lin Y, Xiao X, et al: The anti-Warburg effect elicited by the cAMP-PGC1α pathway drives differentiation of glioblastoma cells into astrocytes. Cell Rep. 23:2832–2833. 2018. View Article : Google Scholar : PubMed/NCBI
31	Goldhoff P, Warrington NM, Limbrick DD Jr, Hope A, Woerner BM, Jackson E, Perry A, Piwnica-Worms D and Rubin JR: Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression. Clin Cancer Res. 14:7717–7725. 2008. View Article : Google Scholar : PubMed/NCBI
32	Lucchi S, Calebiro D, de Filippis T, Grassi ES, Borghi MO and Persani L: 8-Chloro-cyclic AMP and protein kinase A I-selective cyclic AMP analogs inhibit cancer cell growth through different mechanisms. PLoS One. 6:e207852011. View Article : Google Scholar : PubMed/NCBI
33	Cheng YM, Zhu Q, Yao YY, Tang Y, Wang MM and Zou LF: 8-Chloroadenosine 3′,5′-monophosphate induces cell cycle arrest and apoptosis in multiple myeloma cells through multiple mechanisms. Oncol Lett. 4:1384–1388. 2012. View Article : Google Scholar : PubMed/NCBI
34	Grassi ES, Dicitore A, Negri I, Borghi MO, Vitale G and Persani L: 8-Cl-cAMP and PKA I-selective cAMP analogs effectively inhibit undifferentiated thyroid cancer cell growth. Endocrine. 56:388–398. 2017. View Article : Google Scholar : PubMed/NCBI
35	Garcia MA, Solomon DA and Haas-Kogan DA: Exploiting molecular biology for diagnosis and targeted management of pediatric low-grade gliomas. Future Oncol. 12:1493–506. 2016. View Article : Google Scholar : PubMed/NCBI
36	Banerjee RI, Jakacki A, Onar-Thomas S, Wu T, Nicolaides T, Young Poussaint J, Fangusaro J, Phillips A, Perry A, Turner D, et al: A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: A pediatric brain tumor consortium (PBTC) study. Neuro Oncol. 19:1135–1144. 2017. View Article : Google Scholar : PubMed/NCBI
37	Smith AM, Zhang CRZ, Cristino AS, Grady JP, Fink JL and Moore AS: PTEN deletion drives acute myeloid leukemia resistance to MEK inhibitors. Oncotarget. 10:5755–5767. 2019. View Article : Google Scholar : PubMed/NCBI
38	Hur EH, Goo BK, Moon J, Choi Y, Hwang JJ, Kim CS, Bae KS, Choi J, Cho SY, Yang SH, et al: Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells. Oncotarget. 20:41387–41400. 2017. View Article : Google Scholar
39	Lim SY, Menzies AM and Rizos H: Mechanisms and strategies to overcome resistance to molecularly targeted therapy for melanoma. Cancer. 123:21–29. 2017. View Article : Google Scholar
40	Nörz D, Grottke A, Bach J, Herzberger C, Hofmann BT, Nashan B, Jücker M and Ewald F: Discontinuing MEK inhibitors in tumor cells with an acquired resistance increases migration and invasion. Cell Signal. 27:2191–2200. 2015. View Article : Google Scholar : PubMed/NCBI
41	Simeone E, Grimaldi AM, Festino L, Vanella V, Palla M and Ascierto PA: Combination treatment of patients with BRAF-mutant melanoma: A new standard of care. BioDrugs. 31:51–61. 2017. View Article : Google Scholar : PubMed/NCBI
42	Welsh SJ, Rizos H, Scolyer RA and Long GV: Resistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next? Eur J Cancer. 62:76–85. 2016. View Article : Google Scholar : PubMed/NCBI
43	Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, et al: BRAF mutation predicts sensitivity to MEK inhibition. Nature. 439:358–362. 2006. View Article : Google Scholar : PubMed/NCBI
44	Dizdar L, Werner TA, Drusenheimer JC, Möhlendick B, Raba K, Boeck I, Anlauf M, Schott M, Göring W, Esposito I, et al: BRAF^V600E mutation: A promising target in colorectal neuroendocrine carcinoma. Int J Cancer. 144:1379–1390. 2019. View Article : Google Scholar : PubMed/NCBI
45	Gilmartin AG, Bleam MR, Groy A, Moss KG, Minthorn EA, Kulkarni SG, Rominger CM, Erskine S, Fisher KE, Yang J, et al: GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res. 17:989–1000. 2011. View Article : Google Scholar : PubMed/NCBI
46	Catalanotti F, Solit DB, Pulitzer MP, Berger MF, Scott SN, Iyriboz T, Lacouture ME, Panageas KS, Wolchok JD, Carvajal RD, et al: Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma. Clin Cancer Res. 19:2257–2264. 2013. View Article : Google Scholar : PubMed/NCBI
47	Burger MC, Ronellenfitsch W, Lorenz NI, Wagner M, Voss M, Capper D, Tzaridis T, Herrlinger U, Steinbach JP, Stoffels G, et al: Dabrafenib in patients with recurrent, BRAF V600E mutated malignant glioma and leptomeningeal disease. Oncol Rep. 38:3291–3296. 2017.PubMed/NCBI
48	Ranzani M, Alifrangis C, Perna D, Dutton-Regester K, Pritchard A, Wong K, Rashid M, Robles-Espinoza CD, Hayward NK, McDemott U, et al: BRAF/NRAS wild-type melanoma, NF1 status and sensitivity to trametinib. Pigment Cell Melanoma Res. 28:117–119. 2015. View Article : Google Scholar : PubMed/NCBI
49	Ming Z, Lim SY, Kefford RF and Rizos H: Mitogen-activated protein kinase dependency in BRAF/RAS wild-type melanoma: A rationale for combination inhibitors. Pigment Cell Melanoma Res. 33:345–357. 2020. View Article : Google Scholar : PubMed/NCBI
50	Fangusaro J, Onar-Thomas A, Pussaint TY, Wu S, Ligon AH, Lindman N, Banerjee A, Pacher RJ, Kilburn LB, Goldman S, Polack IF, et al: Selumetinb in paedriatic patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrant, refractory, or progressive low-grade glioma: A multicenter, phases 2 trial. Lancet Oncol. 20:1011–1022. 2019. View Article : Google Scholar : PubMed/NCBI
51	Grasso S, Tristante E, Saceda M, Carbonell P, Mayor-López L, Carballo-Santana M, Carrasco-García E, Rocamora-Reverte L, García-Morales P, Carballo F, et al: Resistance to Selumetinib (AZD6244) in colorectal cancer cell lines is mediated by p70S6K and RPS6 activation. Neoplasia. 16:845–860. 2014. View Article : Google Scholar : PubMed/NCBI
52	Tentler JJ, Nallapareddy S, Tan AC, Spreafico A, Pitts TM, Morelli MP, Selby HM, Kachaeva MI, Flanigan SA, Kulikowski GN, et al: Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-mutated colorectal cancer. Mol Cancer Ther. 9:3351–3362. 2010. View Article : Google Scholar : PubMed/NCBI
53	Kerstjens M, Driessen EM, Willekes M, Pinhanços SS, Schneider P, Pieters R and Stam RW: MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations. Oncotarget. 8:14835–14846. 2017. View Article : Google Scholar : PubMed/NCBI
54	Meng J, Peng H, Dai B, Guo W, Wang L, Ji L, Minna JD, Chresta CM, Smith PD, Fang B and Roth JA: High level of AKT activity is associated with resistance to MEK inhibitor AZD6244 (ARRY-142886). Cancer Biol Ther. 8:2073–2080. 2009. View Article : Google Scholar : PubMed/NCBI
55	Sweetlove M, Wrightson E, Kolekar S, Rewcastle GW, Baguley BC, Shepherd PR and Jamieson SM: Inhibitors of pan-PI3K signaling synergize with BRAF or MEK inhibitors to prevent BRAF-mutant melanoma cell growth. Front Oncol. 5:1352015. View Article : Google Scholar : PubMed/NCBI
56	Tsubaki M, Takeda T, Noguchi M, Jinushi M, Seki S, Morii Y, Shimomura K, Imano M, Satou T and Nishida S: Overactivation of Akt contributes to MEK inhibitor primary and acquired resistance in colorectal cancer cells. Cancers (Basel). 25:11–12. 2019.
57	Balmanno K, Chell SD, Gillings AS, Hayat S and Cook SJ: Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and /or strong PI3K signalilling in colorectal cancer cell lines. Int J Cancer. 125:2332–2341. 2009. View Article : Google Scholar : PubMed/NCBI
58	Chen Z, Cheng K, Walton Z, Wang Y, Ebi H, Shimamura T, Liu Y, Tupper T, Ouyang J, Li J, et al: A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature. 483:613–617. 2012. View Article : Google Scholar : PubMed/NCBI
59	Chang T, Krisman K, Theobald EH, Xu J, Akutagawa J, Lauchle JO, Kogan S, Braun BS and Shannon K: Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest. 123:335–339. 2013. View Article : Google Scholar : PubMed/NCBI
60	See WL, Tan IL, Mukherjee J, Nicolaides T and Pieper RO: Sensitivity of glioblastomas to clinically available MEK inhibitors is defined by neurofibromin 1 deficiency. Cancer Res. 72:3350–3359. 2012. View Article : Google Scholar : PubMed/NCBI
61	Nissan MH, Pratilas CA, Jones AM, Ramirez R, Won H, Liu C, Tiwari S, Kong L, Hanrahan AJ, Yao Z, et al: Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res. 74:2340–2350. 2014. View Article : Google Scholar : PubMed/NCBI
62	Whittaker SR, Theurillat JP, Van Allen E, Wagle N, Hsiao J, Cowley GS, Schadendorf D, Root DE and Garraway LA: A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov. 3:350–362. 2013. View Article : Google Scholar : PubMed/NCBI
63	Li Y, Dong Q and Cui Q: Synergistic inhibition of MEK and reciprocal feedback networks for targeted intervention in malignancy. Cancer Biol Med. 16:415–434. 2019.PubMed/NCBI
64	Chen CH, Hsia TC, Yeh MH, Chen TW, Chen YJ, Wei YL, Tu CY and Huang WC: MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK-mediated HER2 phosphorylation at Thr701. Mol Oncol. 11:1273–1287. 2017. View Article : Google Scholar : PubMed/NCBI
65	Iizuka-Ohashi M, Watanabe M, Sukeno M, Morita M, Hoang NTH, Kuchimaru T, Kizaka-Kondoh S, Sowa Y, Sakaguchi K, Taguchi T, et al: Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of Akt in cancer cells. Oncotarget. 9:19597–19612. 2018. View Article : Google Scholar : PubMed/NCBI
66	Coussy F, El Botty R, Lavigne M, Gu C, Fuhrmann L, Briaux A, de Koning L, Dahmani A, Montaudon E, Morisset L, et al: Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers. J Hematol Oncol. 13:132020. View Article : Google Scholar : PubMed/NCBI
67	Liu X, Hu J, Song X, Utpatel K, Zhang Y, Wang P, Lu X, Zhang J, Xu M, Su T, et al: Combined treatment with MEK and mTOR inhibitors is effective in in vitro and in vivo models of hepatocellular carcinoma. Cancers (Basel). 3:9302019. View Article : Google Scholar
68	Ewald F, Nörz D, Grottke A, Bach J, Herzberger C, Hofmann BT, Nashan B and Jücker M: Vertical targeting of AKT and mTOR as well as dual targeting of AKT and MEK signaling is synergistic in hepatocellular carcinoma. J Cancer. 16:1195–1205. 2015. View Article : Google Scholar
69	Meng J, Dai B, Fang B, Bekele BN, Bornmann WG, Sun D, Peng Z, Herbst RS, Papadimitrakopoulou V, Minna JD, et al: Combination treatment with MEK and AKT inhibitors is more effective than each drug alone in human non-small cell lung cancer in vitro and in vivo. PLoS One. 29:e141242010. View Article : Google Scholar
70	Arnold A, Yuan M, Price A, Harris L, Eberhart CG and Raabe EH: Synergistic activity of mTORC1/2 kinase and MEK inhibitors suppresses pediatric low-grade glioma tumorigenicity and vascularity. Neuro Oncol. 22:563–574. 2020. View Article : Google Scholar : PubMed/NCBI
71	Choi KY, Cho YJ, Kim JS, Ahn YH and Hong SH: SHC1 sensitizes cancer cells to the 8-Cl-cAMP treatment. Biochem Biophys Res Commun. 463:673–678. 2015. View Article : Google Scholar : PubMed/NCBI
72	Grbovic O, Jovic V, Ruzdijic S, Pejanovic V, Rakic L and Kanazir S: 8-Cl-cAMP affects glioma cell-cycle kinetics and selectively induces apoptosis. Cancer Invest. 20:972–982. 2002. View Article : Google Scholar : PubMed/NCBI
73	Langeveld CH, Jongenelen CA, Heimans JJ and Stoof JC: Growth inhibition of human glioma cells induced by 8-chloroadenosine, an active metabolite of 8-chloro cyclic adenosine 3′:5′-monophosphate. Cancer Res. 52:3994–3999. 1992.PubMed/NCBI
74	Xing F, Luan Y, Cai J, Wu S, Mai J, Gu J, Zhang H, Li K, Lin Y, Xiao X, et al: The anti-Warburg effect elicited by the cAMP-PGC1α pathway drives differentiation of glioblastoma cells into astrocytes. Cell Rep. 18:468–481. 2017. View Article : Google Scholar : PubMed/NCBI