Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non-Small Cell Lung Cancer.
Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non-Small Cell Lung Cancer.
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DOI：
10.1158/1078-0432.ccr-18-0876
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发表时间：
2018-12-01
期刊：
影响因子：
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通讯作者：
Jänne PA
中科院分区：
文献类型：
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作者：
Bahcall M;Awad MM;Sholl LM;Wilson FH;Xu M;Wang S;Palakurthi S;Choi J;Ivanova EV;Leonardi GC;Ulrich BC;Paweletz CP;Kirschmeier PT;Watanabe M;Baba H;Nishino M;Nagy RJ;Lanman RB;Capelletti M;Chambers ES;Redig AJ;VanderLaan PA;Costa DB;Imamura Y;Jänne PA
MET抑制剂可以有效治疗MET外显子14(METEX 14)突变的非小细胞肺癌(NSCLC)。然而，长期疗效受到耐药性发展的限制。在这项研究中，我们描述了野生型(WT)KRAS的获得性扩增是导致三例METEX 14突变的NSCLC对Crizotinib耐药的分子机制，并提出了针对它的联合治疗。患者来源的细胞系和异种移植(PDX)DFCI358是从WT KRAS大量焦点扩增的耐药METEX 14突变患者肿瘤中建立的。为了研究KRAS介导的抗性机制，我们分析了亲本细胞系及其KRAS siRNA转导产物的分子信号转导机制。评价细胞系对配体刺激的敏感性，并对依赖于KRAS的EGFR配体的表达进行定量。采用细胞存活率和细胞凋亡率检测药物组合在体内和体外的疗效。KRAS扩增是耐药的METEX 14突变型NSCLC中反复发生的遗传事件。该遗传信号的关键特征包括：MET与下游效应分子解偶联，由于PI3K信号的代偿诱导而对双重MET/MEK抑制相对不敏感，KRAS诱导的EGFR配体的表达和对配体依赖和独立激活的超敏，以及在MET抑制时依赖于PI3K信号。利用患者来源的细胞系和异种移植，我们表征了通过KRAS扩增在METEX 14突变的NSCLC中介导的Crizotinib耐药的机制，并展示了MET/PI3K双重抑制作为解决这种耐药机制的治疗策略的优越效果。
MET inhibitors can be effective therapies in patients with MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC). However, long term efficacy is limited by the development of drug resistance. In this study, we characterize acquired amplification of wild type (WT) KRAS as a molecular mechanism behind crizotinib resistance in three cases of METex14 mutant NSCLC and propose a combination therapy to target it. The patient-derived cell line and xenograft (PDX) DFCI358 were established from a crizotinib-resistant METex14 mutant patient tumor with massive focal amplification of WT KRAS. To characterize the mechanism of KRAS-mediated resistance, molecular signaling was analyzed in the parental cell line and its KRAS siRNA-transfected derivative. Sensitivity of the cell line to ligand stimulation was assessed and KRAS-dependent expression of EGFR ligands was quantified. Drug combinations were screened for efficacy in vivo and in vitro using viability and apoptotic assays. KRAS amplification is a recurrent genetic event in crizotinib-resistant METex14 mutant NSCLC. The key characteristics of this genetic signature include uncoupling MET from downstream effectors, relative insensitivity to dual MET/MEK inhibition due to compensatory induction of PI3K signaling, KRAS-induced expression of EGFR ligands and hypersensitivity to ligand-dependent and independent activation, and reliance on PI3K signaling upon MET inhibition. Using patient-derived cell line and xenografts, we characterize the mechanism of crizotinib resistance mediated by KRAS amplification in METex14 mutant NSCLC and demonstrate the superior efficacy of the dual MET/PI3K inhibition as a therapeutic strategy addressing this resistance mechanism.