Acquired Resistance to BRAF Inhibition Can Confer Cross-Resistance to Combined BRAF/MEK Inhibition
Acquired Resistance to BRAF Inhibition Can Confer Cross-Resistance to Combined BRAF/MEK Inhibition
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DOI：
10.1038/jid.2012.63
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发表时间：
2012-07-01
影响因子：
6.5
通讯作者：
Rizos, Helen
中科院分区：
文献类型：
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作者：
Gowrishankar, Kavitha;Snoyman, Stephanie;Rizos, Helen
BRAF激酶的异常激活发生在类似于60%的黑色素瘤中，尽管BRAF抑制剂已显示出显著的早期临床成功，但在大多数患者中发生获得性耐药。对慢性BRAF抑制的抗性通常涉及促分裂原活化蛋白激酶（MAPK）信号转导的再激活，并且BRAF及其下游靶点MAPK/ERK激酶（MEK）的组合靶向可以延迟或克服抗性。为了研究BRAF和MEK抑制的组合的功效，我们产生了对BRAF抑制剂GSK 2118436具有抗性的黑素瘤细胞克隆。这些BRAF耐药亚系通过几种不同的机制获得耐药性，包括获得活化N-RAS突变和COT 1积累增加。这些改变均匀地促进MAPK再活化，并且大多数赋予对MEK抑制以及对BRAF和MEK的同时抑制的抗性。这些数据表明，黑色素瘤肿瘤可能产生异质性耐药机制，其中许多机制将赋予对多种MAPK抑制疗法的耐药性。Journal of Investigative Dermatology（2012）132，1850-1859 doi：10.1038/jid.2012.63; 2012年3月22日在线发表
Aberrant activation of the BRAF kinase occurs in similar to 60% of melanomas, and although BRAF inhibitors have shown significant early clinical success, acquired resistance occurs in most patients. Resistance to chronic BRAF inhibition often involves reactivation of mitogen-activated protein kinase (MAPK) signaling, and the combined targeting of BRAF and its downstream target MAPK/ERK kinase (MEK) may delay or overcome resistance. To investigate the efficacy of combination BRAF and MEK inhibition, we generated melanoma cell clones resistant to the BRAF inhibitor GSK2118436. These BRAF inhibitor-resistant sublines acquired resistance through several distinct mechanisms, including the acquisition of activating N-RAS mutations and increased accumulation of COT1. These alterations uniformly promoted MAPK reactivation and most conferred resistance to MEK inhibition and to the concurrent inhibition of BRAF and MEK. These data indicate that melanoma tumors are likely to develop heterogeneous mechanisms of resistance, many of which will confer resistance to multiple MAPK inhibitory therapies. Journal of Investigative Dermatology (2012) 132, 1850-1859 doi:10.1038/jid.2012.63; published online 22 March 2012