Supplementary Table S4 from The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma

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

doi:10.1158/2159-8290.22530882.v1

Supplementary Table S4 from The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma

journal contribution

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

PDF file, 12065K, Supplementary Table S4. Complete listing of all somatic mutations seen in all tumors. This table provides details on every non-synonymous mutation or short insertion/deletion observed in this cohort, with data on genomic coordinates, protein change, protein region affected, and read counts for each event. Many additional annotations are provided (e.g. cDNA change, RefSeq number)

History

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