MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition

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
Cancer Discovery 2014, 4 (1): 61-8
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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