MET-independent lung cancer cells evading EGFR kinase inhibitors are therapeutically susceptible to BH3 mimetic agents.
MET-independent lung cancer cells evading EGFR kinase inhibitors are therapeutically susceptible to BH3 mimetic agents.
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DOI：
10.1158/0008-5472.can-10-2668
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发表时间：
2011-07-01
期刊：
影响因子：
11.2
通讯作者：
Ma PC
中科院分区：
文献类型：
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作者：
Fan W;Tang Z;Yin L;Morrison B;Hafez-Khayyata S;Fu P;Huang H;Bagai R;Jiang S;Kresak A;Howell S;Vasanji A;Flask CA;Halmos B;Koon H;Ma PC
癌症的靶向治疗固有地受到初始反应后不可避免的耐药疾病复发的限制。为了确定治疗后残留肿瘤细胞内的早期分子变化，我们分析了暴露于可逆或不可逆EGFR抑制剂（单独或与MET激酶抑制剂组合）的药物敏感性肺腺癌细胞系，以表征产生耐药性的适应性反应。显示早期抗性的肿瘤细胞表现出对BCL-2/BCL-XL存活信号传导的MET非依赖性激活的依赖性。此外，这些细胞显示出与极大地延迟细胞增殖和细胞骨架功能相关的静止样状态，这些功能在靶向抑制剂撤回后容易逆转。在异种移植模型中验证了这些发现，证明了在对靶向治疗的初始抗肿瘤反应中存活的残留肿瘤细胞内的BCL-2诱导和p-STAT 3 [Y 705]活化。使用BH 3模拟剂如ABT-737或通过双重RNAi介导的BCL-2/BCL-XL敲低破坏早期存活细胞中的线粒体BCL-2/BCL-XL抗凋亡机制足以根除逃避靶向抑制剂的早期耐药肺肿瘤细胞。同样，在异种移植模型中，用EGFR抑制剂和BH 3模拟物预先联合治疗肺肿瘤细胞根除了早期TKI耐药逃避者，并最终实现了更持久的缓解。我们的研究结果促进了使用BH 3模拟物与靶向受体激酶抑制剂组合的前瞻性临床研究，以优化和改善肺癌治疗的临床结局。
Targeted therapies for cancer are inherently limited by the inevitable recurrence of resistant disease after initial responses. To define early molecular changes within residual tumor cells that persist after treatment, we analyzed drug sensitive lung adenocarcinoma cell lines exposed to reversible or irreversible EGFR inhibitors, alone or in combination with MET kinase inhibitors, to characterize the adaptive response that engenders drug resistance. Tumor cells displaying early resistance exhibited dependence on MET-independent activation of BCL-2/BCL-XL survival signaling. Further, such cells displayed a quiescence-like state associated with greatly retarded cell proliferation and cytoskeletal functions that were readily reversed after withdrawal of targeted inhibitors. Findings were validated in a xenograft model, demonstrating BCL-2 induction and p-STAT3[Y705] activation within the residual tumor cells surviving the initial anti-tumor response to targeted therapies. Disrupting the mitochondrial BCL-2/BCL-XL antiapoptotic machinery in early survivor cells using BH3 mimetic agents such as ABT-737, or by dual RNAi-mediated knockdown of BCL-2/BCL-XL, was sufficient to eradicate the early resistant lung tumor cells evading targeted inhibitors. Similarly, in a xenograft model the preemptive co-treatment of lung tumor cells with an EGFR inhibitor and a BH3 mimetic eradicated early TKI-resistant evaders and ultimately achieved a more durable response with prolonged remission. Our findings prompt prospective clinical investigations using BH3-mimetics combined with targeted receptor kinase inhibitors to optimize and improve clinical outcomes in lung cancer treatment.