转移性黑色素瘤中 RAF 抑制临床耐药的遗传特征。
The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma.
机构信息
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; 2Department of Pathology, Massachusetts General Hospital Cancer Center, Boston; 3Broad Institute of MIT and Harvard; 4Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts; 5Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; 6German Cancer Consortium (DKTK); 7Department of Dermatology, Heidelberg University Hospital, Heidelberg; 8Department of Dermatology and Allergy, Hannover Medical School, Hannover; 9Department of Dermatology, University of Wuerzburg, Wuerzburg; 10Department of Dermatology, Venerology and Allergology, University of Schleswig-Holstein Hospital, Kiel; 11Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich; 12Department of Dermatology, Venerology and Allergy, Charité Universitätsmedizin Berlin, Humboldt University, Berlin; 13Department of Dermatology, University of Mainz, Mainz; 14University Medical Center, University of Tübingen, Tübingen, Germany; 15Department of Genome Sciences, University of Washington, Seattle, Washington; 16Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; and 17First Department of Medicine, Medical School, University of Athens, Athens, Greece.
出版信息
Cancer Discov. 2014 Jan;4(1):94-109. doi: 10.1158/2159-8290.CD-13-0617. Epub 2013 Nov 21.
Most patients with BRAF(V600)-mutant 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 tumors from 45 patients with BRAF(V600)-mutant 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 mitogen-activated protein kinase (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 BRAF(V600)-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.
大多数 BRAF(V600)-突变转移性黑色素瘤患者对选择性 RAF 激酶抑制剂产生耐药性。RAF 抑制剂的临床遗传耐药机制谱和挽救治疗选择尚不完全清楚。我们对 45 例接受维莫非尼或达拉非尼单药治疗的 BRAF(V600)-突变转移性黑色素瘤患者的福尔马林固定、石蜡包埋肿瘤进行了全外显子组测序。在 45 例患者中的 23 例（51%）观察到已知或推测的 RAF 抑制剂耐药基因的遗传改变。除了先前描述的改变外，我们还发现了一种“长尾”新丝裂原活化蛋白激酶（MAPK）通路改变（MAP2K2、MITF），它们赋予 RAF 抑制剂耐药性。在三种情况下，同一肿瘤活检中观察到多个耐药基因改变。总的来说，RAF 抑制剂治疗导致了多种临床遗传耐药机制，主要涉及 MAPK 通路的重新激活。可能需要新的治疗组合来实现对 BRAF(V600)-突变黑色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，可能会对后续的耐药性研究进行建模。
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