RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer.
RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer.
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DOI：
10.1038/nm.3930
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发表时间：
2015-09
期刊：
影响因子：
82.9
通讯作者：
Bivona TG
中科院分区：
文献类型：
--
作者：
Hrustanovic G;Olivas V;Pazarentzos E;Tulpule A;Asthana S;Blakely CM;Okimoto RA;Lin L;Neel DS;Sabnis A;Flanagan J;Chan E;Varella-Garcia M;Aisner DL;Vaishnavi A;Ou SH;Collisson EA;Ichihara E;Mack PC;Lovly CM;Karachaliou N;Rosell R;Riess JW;Doebele RC;Bivona TG
对抗癌症耐药性的一种策略是预先部署合理的综合治疗，抑制耐药肿瘤细胞的存活和出现。在此，我们在ALK和EML 4致癌融合的肺腺癌模型中证明，肿瘤细胞存活需要GTATRAS-丝裂原活化蛋白激酶（MAPK）途径，而不是其他已知的ALK效应物。EML 4-ALK通过EML 4的HELP结构域结合所有三种主要RAS亚型来激活RAS-MAPK信号传导。MAPK通路的重新激活（通过编码野生型K-RAS（KRASWT）的基因拷贝数增加或MAPK磷酸酶DUSP 6表达降低）在体外促进了对ALK抑制剂的耐药性，并且每一种都与EML 4-ALK阳性肺腺癌个体对ALK抑制剂的耐药性相关。在EML 4-ALK肺腺癌临床前模型中，ALK和激酶MEK的前期抑制可增强初始缓解的幅度和持续时间。我们的研究结果确定RAS-MAPK依赖性是EML 4-ALK肺腺癌的标志，并为预先抑制ALK和MEK以预防耐药性和改善患者结局提供了理论基础。
One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS–mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRASWT) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK–positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.