title: The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma.
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.
authors.affiliation: 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; 2Department of Pathology, Massachusetts General Hospital Cancer Center, Boston; 3Broad Institute of MIT and Harvard; 4Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts; 5Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; 6German Cancer Consortium (DKTK); 7Department of Dermatology, Heidelberg University Hospital, Heidelberg; 8Department of Dermatology and Allergy, Hannover Medical School, Hannover; 9Department of Dermatology, University of Wuerzburg, Wuerzburg; 10Department of Dermatology, Venerology and Allergology, University of Schleswig-Holstein Hospital, Kiel; 11Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich; 12Department of Dermatology, Venerology and Allergy, Charité Universitätsmedizin Berlin, Humboldt University, Berlin; 13Department of Dermatology, University of Mainz, Mainz; 14University Medical Center, University of Tübingen, Tübingen, Germany; 15Department of Genome Sciences, University of Washington, Seattle, Washington; 16Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; and 17First Department of Medicine, Medical School, University of Athens, Athens, Greece.
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.forename: Antje
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authors.lastname: Sucker
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Treacy
authors.forename: Cory M
authors.initials: CM
authors.lastname: Johannessen
authors.forename: Eva M
authors.initials: EM
authors.lastname: Goetz
authors.forename: Chelsea S
authors.initials: CS
authors.lastname: Place
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.forename: Steven
authors.initials: S
authors.lastname: Whittaker
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Kryukov
authors.forename: Eran
authors.initials: E
authors.lastname: Hodis
authors.forename: Mara
authors.initials: M
authors.lastname: Rosenberg
authors.forename: Aaron
authors.initials: A
authors.lastname: McKenna
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.forename: Deborah
authors.initials: D
authors.lastname: Farlow
authors.forename: Lisa
authors.initials: L
authors.lastname: Zimmer
authors.forename: Uwe
authors.initials: U
authors.lastname: Hillen
authors.forename: Ralf
authors.initials: R
authors.lastname: Gutzmer
authors.forename: Simone M
authors.initials: SM
authors.lastname: Goldinger
authors.forename: Selma
authors.initials: S
authors.lastname: Ugurel
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Gogas
authors.forename: Friederike
authors.initials: F
authors.lastname: Egberts
authors.forename: Carola
authors.initials: C
authors.lastname: Berking
authors.forename: Uwe
authors.initials: U
authors.lastname: Trefzer
authors.forename: Carmen
authors.initials: C
authors.lastname: Loquai
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Hassel
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059472:Exome; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D048370:MAP Kinase Kinase 2 / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D010091:Oximes / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics*; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D010091:Oximes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D013449:Sulfonamides; D000077484:Vemurafenib; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; C482125:MAP2K1 protein, human; C561627:dabrafenib