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    The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic MelanomaEliezer 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, and Dirk SchadendorfMost 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.doi: 10.1158/2159-8290.CD-13-0631MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK InhibitionNikhil 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, and Levi A. GarrawayTreatment 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-transc**tome 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 （MEK2Q60P）。 MEK2Q60P 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