Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling
Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling
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DOI：
10.1200/jco.2010.33.2312
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发表时间：
2011-08-01
影响因子：
45.3
通讯作者：
Garraway, Levi A.
中科院分区：
文献类型：
--
作者：
Wagle, Nikhil;Emery, Caroline;Garraway, Levi A.
对肿瘤对靶向抗癌药物产生耐药性的机制的详细了解将加快具有持久临床疗效的治疗策略的发展。RAF在braf突变黑色素瘤中的抑制体现了许多靶向药物的前景和挑战；虽然应答率很高，但总会产生耐药性。在这里，我们阐明了对激酶抑制剂耐药的总体原则，以及通过肿瘤突变谱在临床环境中表征耐药的翻译方法。作为原理证明，我们对一名黑色素瘤患者的肿瘤进行了靶向性、大规模平行测序，该患者在最初的显著反应后对PLX4032产生了耐药性。结果发现下游激酶MEK1密码子121处存在激活突变，而在相应的预处理肿瘤中不存在。MEK1（C121S）突变被证明可以增加激酶活性，并在体外对RAF和MEK抑制具有强大的抗性。因此，预计MEK1（C121S）或功能类似的突变会对MEK/RAF联合抑制产生耐药性。这些结果为评估获得性抵抗激酶抑制的机制提供了一个有指导意义的框架，并说明了新兴技术在加速个性化癌症药物方面的应用。中华临床杂志29:3085-3096。(C) 2011年美国临床肿瘤学会
A detailed understanding of the mechanisms by which tumors acquire resistance to targeted anticancer agents should speed the development of treatment strategies with lasting clinical efficacy. RAF inhibition in BRAF-mutant melanoma exemplifies the promise and challenge of many targeted drugs; although response rates are high, resistance invariably develops. Here, we articulate overarching principles of resistance to kinase inhibitors, as well as a translational approach to characterize resistance in the clinical setting through tumor mutation profiling. As a proof of principle, we performed targeted, massively parallel sequencing of 138 cancer genes in a tumor obtained from a patient with melanoma who developed resistance to PLX4032 after an initial dramatic response. The resulting profile identified an activating mutation at codon 121 in the downstream kinase MEK1 that was absent in the corresponding pretreatment tumor. The MEK1(C121S) mutation was shown to increase kinase activity and confer robust resistance to both RAF and MEK inhibition in vitro. Thus, MEK1(C121S) or functionally similar mutations are predicted to confer resistance to combined MEK/RAF inhibition. These results provide an instructive framework for assessing mechanisms of acquired resistance to kinase inhibition and illustrate the use of emerging technologies in a manner that may accelerate personalized cancer medicine. J Clin Oncol 29: 3085-3096. (C) 2011 by American Society of Clinical Oncology