Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma.
Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma.
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DOI：
10.1158/2159-8290.cd-12-0417
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发表时间：
2013-03
期刊：
影响因子：
28.2
通讯作者：
Ellisen LW
中科院分区：
文献类型：
--
作者：
He L;Torres-Lockhart K;Forster N;Ramakrishnan S;Greninger P;Garnett MJ;McDermott U;Rothenberg SM;Benes CH;Ellisen LW
鳞状细胞癌(SCC)缺乏有效的靶向治疗。在这里，我们发现Mcl-1在鳞癌中是一种主要的和组织特异性的生存因子，为新的治疗方法提供了路线图。用HDAC抑制剂Vorinostat处理可调节Bcl-2家族成员的表达，使Mcl-1轴失活，从而诱导SCC细胞凋亡。尽管Mcl-1的优势使SCC细胞对BH3模拟ABT-737具有抗药性，但voinostat通过将Bim从Mcl-1穿梭到Bcl-2/Bcl-xl使它们对ABT-737的敏感性增强，导致这种组合的戏剧性协同作用和体内肿瘤的持续消退。此外，鳞状细胞癌中的体细胞FBW7突变与稳定的Mcl-1和高Bim水平有关，导致对标准化疗的反应较差，但对HDAC抑制剂的反应强劲，并与旋转剂/ABT-737联合应用增强了协同作用。总而言之，我们的发现为这种联合治疗在鳞癌中的应用提供了生化基础和预测标记物。
Effective targeted therapeutics for squamous cell carcinoma (SCC) are lacking. Here we uncover Mcl-1 as a dominant and tissue-specific survival factor in SCC, providing a roadmap for a new therapeutic approach. Treatment with the HDAC inhibitor vorinostat regulates Bcl-2 family member expression to disable the Mcl-1 axis and thereby induce apoptosis in SCC cells. Although Mcl-1 dominance renders SCC cells resistant to the BH3 mimetic ABT-737, vorinostat primes them for sensitivity to ABT-737 by shuttling Bim from Mcl-1 to Bcl-2/Bcl-xl, resulting in dramatic synergy for this combination and sustained tumor regression in vivo. Moreover, somatic FBW7 mutation in SCC is associated with stabilized Mcl-1 and high Bim levels, resulting in a poor response to standard chemotherapy but a robust response to HDAC inhibitors and enhanced synergy with combination vorinostat/ABT-737. Collectively, our findings provide a biochemical rationale and predictive markers for the application of this therapeutic combination in SCC.