Inhibition of BET bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptotic agents.
Non-small cell lung cancer (NSCLC) has the highest incidence of cancer-related death worldwide and a high medical need for more effective therapies. Small-molecule inhibitors of the bromodomain and extra terminal domain (BET) family such as JQ1, I-BET762 and OTX-015 are active in a wide range of different cancer types, including lung cancer. Although their activity on oncogene expression such as c-Myc has been addressed in many studies, the effects of BET inhibition on the apoptotic pathway remain largely unknown. Here we evaluated the activity of BET bromodomain inhibitors on cell cycle distribution and on components of the apoptosis response. Using a panel of 12 KRAS-mutated NSCLC models, we found that cell lines responsive to BET inhibitors underwent apoptosis and reduced their S-phase population, concomitant with downregulation of c-Myc expression. Conversely, ectopic c-Myc overexpression rescued the anti-proliferative effect of JQ1. In the H1373 xenograft model, treatment with JQ1 significantly reduced tumor growth and downregulated the expression of c-Myc. The effects of BET inhibition on the expression of 370 genes involved in apoptosis were compared in sensitive and resistant cells and we found the expression of the two key apoptosis regulators FLIP and XIAP to be highly BET dependent. Consistent with this, combination treatment of JQ1 with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the pro-apoptotic chemotherapeutic agent cisplatin enhanced induction of apoptosis in both BET inhibitor sensitive and resistant cells. Further we showed that combination of JQ1 with cisplatin led to significantly improved anti-tumor efficacy in A549 tumor-bearing mice. Altogether, these results show that the identification of BET-dependent genes provides guidance for the choice of drug combinations in cancer treatment. They also demonstrate that BET inhibition primes NSCLC cells for induction of apoptosis and that a combination with pro-apoptotic compounds represents a valuable strategy to overcome treatment resistance.
Drug Discovery, Bayer Pharma AG, Berlin, Germany.|Institut für Biologie, Humboldt-Universität zu Berlin, Berlin, Germany.
Olaf
O
Klingbeil
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Ralf
R
Lesche
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Kathy A
KA
Gelato
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Bernard
B
Haendler
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Pascale
P
Lejeune
D000072283:A549 Cells; D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016513:Mice, SCID; D009154:Mutation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C561695:(+)-JQ1 compound; D000083:Acetanilides; D001381:Azepines; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D006575:Heterocyclic Compounds, 3-Ring; C117307:KRAS protein, human; C489427:MYC protein, human; C000605331:OTX015; D016271:Proto-Oncogene Proteins c-myc; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014230:Triazoles; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D001569:Benzodiazepines; C554645:molibresib; D016283:Proto-Oncogene Proteins p21(ras); D002945:Cisplatin