@article{3160297,
    title = "The Genetic Landscape of Clinical Resistance to RAF Inhibition in
Metastatic Melanoma",
    author = "Van Allen, Eliezer M. and Wagle, Nikhil and Sucker, Antje and Treacy, and Daniel J. and Johannessen, Cory M. and Goetz, Eva M. and Place, Chelsea and S. and Taylor-Weiner, Amaro and Whittaker, Steven and Kryukov, Gregory and V. and Hodis, Eran and Rosenberg, Mara and McKenna, Aaron and Cibulskis, and Kristian and Farlow, Deborah and Zimmer, Lisa and Hillen, Uwe and and Gutzmer, Ralf and Goldinger, Simone M. and Ugurel, Selma and Gogas, and Helen J. and Egberts, Friederike and Berking, Carola and Trefzer, Uwe and and Loquai, Carmen and Weide, Benjamin and Hassel, Jessica C. and and Gabriel, Stacey B. and Carter, Scott L. and Getz, Gad and Garraway, Levi and A. and Schadendorf, Dirk and Dermatologic Cooperative Oncology",
    journal = "Cancer Discovery",
    year = "2014",
    volume = "4",
    number = "1",
    pages = "94-109",
    publisher = "AMER ASSOC CANCER RESEARCH",
    issn = "2159-8274, 2159-8290",
    doi = "10.1158/2159-8290.CD-13-0617",
    abstract = "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.
SIGNIFICANCE: The use of RAF inhibitors for BRAF(V600)-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.
(C)2013 AACR."
}