Klingbeil Olaf, Lesche Ralf, Gelato Kathy A, Haendler Bernard, Lejeune Pascale
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Institut für Biologie, Humboldt-Universität zu Berlin, Berlin, Germany.
Cell Death Dis. 2016 Sep 8;7(9):e2365. doi: 10.1038/cddis.2016.271.
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.
非小细胞肺癌（NSCLC）在全球癌症相关死亡中发病率最高，对更有效治疗方法的医疗需求很高。溴结构域和额外末端结构域（BET）家族的小分子抑制剂，如JQ1、I-BET762和OTX-015，在包括肺癌在内的多种不同癌症类型中具有活性。尽管它们对癌基因表达（如c-Myc）的作用已在许多研究中得到探讨，但BET抑制对凋亡途径的影响仍 largely未知。在这里，我们评估了BET溴结构域抑制剂对细胞周期分布和凋亡反应成分的活性。使用一组12个KRAS突变的NSCLC模型，我们发现对BET抑制剂有反应的细胞系发生凋亡并减少其S期群体，同时c-Myc表达下调。相反，异位c-Myc过表达挽救了JQ1的抗增殖作用。在H1373异种移植模型中，用JQ1治疗显著降低肿瘤生长并下调c-Myc的表达。在敏感和耐药细胞中比较了BET抑制对370个参与凋亡的基因表达的影响，我们发现两个关键凋亡调节因子FLIP和XIAP的表达高度依赖BET。与此一致，JQ1与肿瘤坏死因子相关凋亡诱导配体（TRAIL）或促凋亡化疗药物顺铂联合治疗增强了BET抑制剂敏感和耐药细胞中的凋亡诱导。此外，我们表明JQ1与顺铂联合使用在携带A549肿瘤的小鼠中导致显著提高的抗肿瘤疗效。总之，这些结果表明，鉴定BET依赖性基因可为癌症治疗中药物组合的选择提供指导。它们还证明，BET抑制使NSCLC细胞易于诱导凋亡，并且与促凋亡化合物联合使用是克服治疗耐药性的一种有价值的策略。
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