Περίληψη:
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.
Συγγραφείς:
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 and
Gutzmer, Ralf
Goldinger, Simone M.
Ugurel, Selma
Gogas,
Helen J.
Egberts, Friederike
Berking, Carola
Trefzer, Uwe
and Loquai, Carmen
Weide, Benjamin
Hassel, Jessica C. and
Gabriel, Stacey B.
Carter, Scott L.
Getz, Gad
Garraway, Levi
A.
Schadendorf, Dirk
Dermatologic Cooperative Oncology
