ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors.
ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors.
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DOI：
10.1158/0008-5472.can-14-2073
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发表时间：
2014-12-01
期刊：
影响因子：
11.2
通讯作者：
Garraway LA
中科院分区：
文献类型：
--
作者：
Goetz EM;Ghandi M;Treacy DJ;Wagle N;Garraway LA
使用针对 BRAFV600 突变的转移性黑色素瘤的靶向治疗可改善许多患者的无进展生存期；然而，获得性耐药性仍然是一个重大的医学挑战。到目前为止，最常见的临床耐药机制涉及通过多种机制重新激活 MAPK (RAF/MEK/ERK) 通路。因此，靶向 ERK 本身已成为一个有吸引力的治疗概念，并且几种 ERK 抑制剂已进入临床试验。我们试图先发制人地确定 ERK1/2 中的突变，这些突变会赋予 BRAFV600 突变黑色素瘤对 ERK 抑制剂或 RAF/MEK 联合抑制的抗性。通过随机诱变筛选，我们发现了 ERK1 (MAPK3) 和 ERK2 (MAPK1) 中的多个点突变，这些点突变可能赋予对 ERK 或 RAF/MEK 抑制剂的抗性。 ERK 抑制剂耐药等位基因对 RAF/MEK 抑制剂敏感，反之亦然，这表明未来开发交替的 RAF/MEK 和 ERK 抑制剂方案可能有助于规避对这些药物的耐药性。
The use of targeted therapeutics directed against BRAFV600-mutant metastatic melanoma improves progression-free survival in many patients; however, acquired drug resistance remains a major medical challenge. By far, the most common clinical resistance mechanism involves reactivation of the MAPK (RAF/MEK/ERK) pathway by a variety of mechanisms. Thus, targeting ERK itself has emerged as an attractive therapeutic concept, and several ERK inhibitors have entered clinical trials. We sought to preemptively determine mutations in ERK1/2 that confer resistance to either ERK inhibitors or combined RAF/MEK inhibition in BRAFV600-mutant melanoma. Using a random mutagenesis screen, we identified multiple point mutations in ERK1 (MAPK3) and ERK2 (MAPK1) that could confer resistance to ERK or RAF/MEK inhibitors. ERK inhibitor–resistant alleles were sensitive to RAF/ MEK inhibitors and vice versa, suggesting that the future development of alternating RAF/MEK and ERK inhibitor regimens might help circumvent resistance to these agents.