Choudhary G S, Al-Harbi S, Mazumder S, Hill B T, Smith M R, Bodo J, Hsi E D, Almasan A
1] Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA [2] Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Cell Death Dis. 2015 Jan 15;6(1):e1593. doi: 10.1038/cddis.2014.525.
Overexpression of anti-apoptotic BCL-2 family members is a hallmark of many lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) that can be targeted with small molecule inhibitors. ABT-199 is a rationally designed BCL-2 homology (BH)-3 mimetic that specifically binds to BCL-2, but not to MCL-1 and BCL-xL. Although the thrombocytopenia that occurs with navitoclax treatment has not been a problem with ABT-199, clinical trials in CLL could benefit by lowering the ABT-199 concentration through targeting other survival pathways. In this study, we investigated the mechanisms of resistance that develops to ABT-199 therapy by generating ABT-199-resistant (ABT199-R) cell lines via chronic exposure of NHL cell lines to ABT-199. Acquired resistance resulted in substantial AKT activation and upregulation of MCL-1 and BCL-xL levels that sequestered BIM. ABT199-R cells exhibited increased MCL-1 stability and failed to activate BAX in response to ABT-199. The ABT-199 acquired and inherent resistant cells were sensitized to treatment with ABT-199 by inhibitors of the PI3K, AKT, and mTOR pathways, NVP-BEZ235 and GS-1101. NVP-BEZ235, a dual inhibitor of p-AKT and mTOR, reduced MCL-1 levels causing BIM release from MCL-1 and BCL-xL, thus leading to cell death by BAX activation. The PI3Kδ inhibitor GS-1101 (idelalisib) downregulated MCL-1 and sensitized ABT199-R cells through AKT-mediated BAX activation. A genetic approach, through siRNA-mediated down-regulation of AKT, MCL-1, and BCL-xL, significantly decreased cell survival, demonstrating the importance of these cell survival factors for ABT-199 resistance. Our findings suggest a novel mechanism that modulates the expression and activity of pro-survival proteins to confer treatment resistance that could be exploited by a rational combination therapeutic regimen that could be effective for treating lymphoid malignancies.
抗凋亡BCL-2家族成员的过表达是许多淋巴系统恶性肿瘤的一个标志，包括慢性淋巴细胞白血病（CLL）和非霍奇金淋巴瘤（NHL），这些肿瘤可用小分子抑制剂进行靶向治疗。ABT-199是一种经过合理设计的BCL-2同源结构域（BH）-3模拟物，它能特异性结合BCL-2，但不与MCL-1和BCL-xL结合。虽然纳武单抗治疗时出现的血小板减少在ABT-199治疗中并非问题，但CLL的临床试验通过靶向其他生存途径降低ABT-199浓度可能会受益。在本研究中，我们通过使NHL细胞系长期暴露于ABT-199来生成ABT-199耐药（ABT199-R）细胞系，从而研究对ABT-199治疗产生耐药的机制。获得性耐药导致AKT大量激活以及MCL-1和BCL-xL水平上调，从而隔离了BIM。ABT199-R细胞表现出MCL-1稳定性增加，并且在ABT-199作用下未能激活BAX。PI3K、AKT和mTOR通路的抑制剂NVP-BEZ235和GS-1101使ABT-199获得性耐药和固有耐药细胞对ABT-199治疗敏感。NVP-BEZ235是一种p-AKT和mTOR的双重抑制剂，可降低MCL-1水平，导致BIM从MCL-1和BCL-xL中释放，从而通过激活BAX导致细胞死亡。PI3Kδ抑制剂GS-1101（idelalisib）下调MCL-1并通过AKT介导的BAX激活使ABT199-R细胞敏感。通过siRNA介导的AKT、MCL-1和BCL-xL下调的基因方法显著降低了细胞存活率，证明了这些细胞存活因子对ABT-199耐药的重要性。我们的研究结果提示了一种调节促生存蛋白表达和活性以赋予治疗耐药性的新机制，这可通过一种合理的联合治疗方案来利用，该方案可能对治疗淋巴系统恶性肿瘤有效。
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