获得性耐药的可调组合机制限制了 BRAF/MEK 共靶向治疗的疗效，但导致黑色素瘤药物成瘾。
Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction.
机构信息
Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
出版信息
Cancer Cell. 2015 Feb 9;27(2):240-56. doi: 10.1016/j.ccell.2014.11.018. Epub 2015 Jan 15.
Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. (V600E)BRAF, expressed at supraphysiological levels because of (V600E)BRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed (V600E)BRAF via a regulatory interface at R662 of (V600E)BRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.
联合 BRAF 和 MEK 靶向治疗优于 BRAF 抑制剂（BRAFi）治疗，但仍存在获得性耐药。我们发现黑色素瘤通过增强或组合单药 BRAFi 耐药的机制来获得对联合 BRAF 和 MEK 抑制的耐药性。这些双重耐药相关的遗传构型显著改变了 MAPK 通路重新激活的分子相互作用。由于(V600E)BRAF 超扩增，表达水平高于生理水平的(V600E)BRAF 与 CRAF 二聚化并激活 CRAF。此外，MEK 突变体通过(V600E)BRAF 的 R662 处的调节界面增强与过表达(V600E)BRAF 的相互作用。重要的是，对 BRAFi+MEKi 耐药而不是对 BRAFi 单独耐药的黑色素瘤细胞系表现出强烈的药物成瘾性，这为潜在的可利用治疗机会提供了依据。
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