Supplementary Table S3 from The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma

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posted on 2023-04-03, 20:50 authored by Eliezer M. Van Allen, Nikhil Wagle, Antje Sucker, Daniel J. Treacy, Cory M. Johannessen, Eva M. Goetz, Chelsea S. Place, Amaro Taylor-Weiner, Steven Whittaker, Gregory V. Kryukov, Eran Hodis, Mara Rosenberg, Aaron McKenna, Kristian Cibulskis, Deborah Farlow, Lisa Zimmer, Uwe Hillen, Ralf Gutzmer, Simone M. Goldinger, Selma Ugurel, Helen J. Gogas, Friederike Egberts, Carola Berking, Uwe Trefzer, Carmen Loquai, Benjamin Weide, Jessica C. Hassel, Stacey B. Gabriel, Scott L. Carter, Gad Getz, Levi A. Garraway, Dirk Schadendorf

XLSX file 261K, Supplementary Table S3. Mutations seen in patients with tumors at one time point. For patients with whole exome sequencing data on either pre-treatment (for early resistance cases) or after relapse (for acquired resistance cases), this table summarizes the complete set of non-synonymous mutations and short insertion/deletions called. Alterations in this table met the additional criteria of at least 30X coverage in the tumor and an allelic fraction of at least 0.05. Each column is a patient, each row is a gene, and each non-blank entry denotes the protein change that results from the mutation seen

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ARTICLE ABSTRACT

Most patients with BRAFV600-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 BRAFV600-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 BRAFV600-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.Significance: The use of RAF inhibitors for BRAFV600-mutant metastatic melanoma improves patient outcomes, but most patients demonstrate early or acquired resistance to this targeted therapy. We reveal the genetic landscape of clinical resistance mechanisms to RAF inhibitors from patients using whole-exome sequencing, and experimentally assess new observed mechanisms to define potential subsequent treatment strategies. Cancer Discov; 4(1); 94–109. ©2013 AACR.See related commentary by Solit and Rosen, p. 27This article is highlighted in the In This Issue feature, p. 1