The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma.
The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma.
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DOI：
10.1158/2159-8290.cd-13-0617
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发表时间：
2014-01
期刊：
影响因子：
28.2
通讯作者：
Dermatologic Cooperative Oncology Group of Germany (DeCOG)
中科院分区：
文献类型：
--
作者：
Van Allen EM;Wagle N;Sucker A;Treacy DJ;Johannessen CM;Goetz EM;Place CS;Taylor-Weiner A;Whittaker S;Kryukov GV;Hodis E;Rosenberg M;McKenna A;Cibulskis K;Farlow D;Zimmer L;Hillen U;Gutzmer R;Goldinger SM;Ugurel S;Gogas HJ;Egberts F;Berking C;Trefzer U;Loquai C;Weide B;Hassel JC;Gabriel SB;Carter SL;Getz G;Garraway LA;Schadendorf D;Dermatologic Cooperative Oncology Group of Germany (DeCOG)
大多数BRAFV 600转移性黑色素瘤患者对选择性RAF激酶抑制剂产生耐药性。对RAF抑制剂的临床遗传耐药机制和挽救治疗的选择还不完全清楚。我们对45例接受维罗非尼或达拉非尼单药治疗的BRAFV 600转移性黑色素瘤患者的福尔马林固定、石蜡包埋（FFPE）肿瘤进行了全外显子组测序。45例患者中有23例（51%）观察到已知或推定的RAF抑制剂耐药基因的遗传变异。除了先前表征的改变之外，我们发现了赋予RAF抑制剂抗性的新MAPK通路改变（MAP2K2，MITF）的“长尾”。在3例病例中，在同一肿瘤活检中观察到多个耐药基因改变。总的来说，RAF抑制剂治疗导致不同的临床遗传耐药机制，主要涉及MAPK通路的再激活。可能需要新的治疗组合来实现BRAFV 600黑素瘤的持久临床控制。将临床基因组学与临床前筛选相结合可以为后续的耐药性研究建模。
Most patients with BRAFV600 metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole exome sequencing on formalin-fixed, paraffin embedded (FFPE) tumors from 45 patients with BRAFV600 metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a “long tail” of new MAPK pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAFV600 melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.