MAP Kinase Pathway Alterations in BRAF-mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition

Overview

Journal Cancer Discov

Specialty Oncology

Date 2013 Nov 23

PMID 24265154

Citations 282

Authors

Nikhil Wagle

Eliezer M Van Allen

Daniel J Treacy

Dennie T Frederick

Zachary A Cooper

Amaro Taylor-Weiner

Mara Rosenberg

Eva M Goetz

Ryan J Sullivan

Deborah N Farlow

Dennis C Friedrich

Kristin Anderka

Danielle Perrin

Cory M Johannessen

Aaron McKenna

Kristian Cibulskis

Gregory Kryukov

Eran Hodis

Donald P Lawrence

Sheila Fisher

Gad Getz

Stacey B Gabriel

Scott L Carter

Keith T Flaherty

Jennifer A Wargo

Levi A Garraway

Affiliations

Soon will be listed here.

Abstract

Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.

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