title: Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy.
abstract: BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAF(V600)-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses.
authors.affiliation: Division of Dermatology, Department of Medicine.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: Hubing
authors.initials: H
authors.lastname: Shi
authors.affiliation: Division of Dermatology, Department of Medicine.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: Willy
authors.initials: W
authors.lastname: Hugo
authors.affiliation: Division of Dermatology, Department of Medicine.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: Xiangju
authors.initials: X
authors.lastname: Kong
authors.affiliation: Division of Dermatology, Department of Medicine.|Department of Molecular and Medical Pharmacology.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: Aayoung
authors.initials: A
authors.lastname: Hong
authors.affiliation: Division of Surgical Oncology, Department of Surgery.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Koya
authors.affiliation: Division of Dermatology, Department of Medicine.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: Gatien
authors.initials: G
authors.lastname: Moriceau
authors.affiliation: Division of Hematology & Oncology, Department of Medicine.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: Thinle
authors.initials: T
authors.lastname: Chodon
authors.affiliation: Division of Hematology & Oncology, Department of Medicine.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: Rongqing
authors.initials: R
authors.lastname: Guo
authors.affiliation: Department of Medicine.|Vanderbilt-Ingram Cancer Center, Nashville, TN 37232.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Department of Cancer Biology.|Vanderbilt-Ingram Cancer Center, Nashville, TN 37232.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Dahlman
authors.affiliation: Department of Surgery.|Vanderbilt-Ingram Cancer Center, Nashville, TN 37232.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kelley
authors.affiliation: Melanoma Institute of Australia, Westmead Millenium Institute, Westmead Hospital, University of Sydney, New South Wales, Australia.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: Division of Hematology & Oncology, Department of Medicine.|Jonsson Comprehensive Cancer Center.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.affiliation: Division of Hematology & Oncology, Department of Medicine.|Jonsson Comprehensive Cancer Center.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Glaspy
authors.affiliation: Department of Medicine.|Vanderbilt-Ingram Cancer Center, Nashville, TN 37232.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: van Baren
authors.affiliation: Melanoma Institute of Australia, Westmead Millenium Institute, Westmead Hospital, University of Sydney, New South Wales, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Division of Dermatology, Department of Medicine.|Division of Hematology & Oncology, Department of Medicine.|Jonsson Comprehensive Cancer Center.|Department of Molecular and Medical Pharmacology.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Division of Dermatology, Department of Medicine.|Jonsson Comprehensive Cancer Center.|Department of Molecular and Medical Pharmacology.|David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D060965:Clonal Evolution; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010091:Oximes / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D019869:Phosphatidylinositol 3-Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins; C561627:dabrafenib