BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors.
BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors.
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DOI：
10.1158/2159-8290.cd-11-0106
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发表时间：
2011-09
期刊：
影响因子：
28.2
通讯作者：
Engelman JA
中科院分区：
文献类型：
--
作者：
Faber AC;Corcoran RB;Ebi H;Sequist LV;Waltman BA;Chung E;Incio J;Digumarthy SR;Pollack SF;Song Y;Muzikansky A;Lifshits E;Roberge S;Coffman EJ;Benes CH;Gómez HL;Baselga J;Arteaga CL;Rivera MN;Dias-Santagata D;Jain RK;Engelman JA
具有特定基因突变的癌症易受选择性激酶抑制剂的影响。然而，在具有相同致敏基因突变的癌症中，有广泛的益处。在此，我们测量了在使用相应的激酶抑制剂治疗后，具有相同驱动癌基因的细胞系之间的凋亡率。尽管激酶抑制剂对靶细胞和相关的下游信号通路有类似的抑制作用，但仍存在广泛的激酶抑制剂诱导的细胞凋亡。令人惊讶的是，预处理前BH3-only促凋亡BIM的RNA水平可以预测EGFR、HER2和PI3K抑制剂分别诱导EGFR突变、HER2扩增和PIK3CA突变癌症细胞凋亡的能力，但BIM水平不能预测对标准化疗的反应。此外，EGFR突变肺癌标本中的BIM RNA水平预测了EGFR抑制剂的反应和临床获益的持续时间。这些发现表明，对治疗naïve肿瘤活检中BIM水平的评估可能表明单药激酶抑制剂在多种癌基因成瘾范例中的获益程度。
Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pre-treatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR mutant, HER2 amplified, and PIK3CA mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms.