title: Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction.
abstract: Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. (V600E)BRAF, expressed at supraphysiological levels because of (V600E)BRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed (V600E)BRAF via a regulatory interface at R662 of (V600E)BRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Gatien
authors.initials: G
authors.lastname: Moriceau
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Willy
authors.initials: W
authors.lastname: Hugo
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Aayoung
authors.initials: A
authors.lastname: Hong
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Hubing
authors.initials: H
authors.lastname: Shi
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xiangju
authors.initials: X
authors.lastname: Kong
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Clarissa C
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Division of Oncology, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Koya
authors.affiliation: Discovery Oncology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Samatar
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Negar
authors.initials: N
authors.lastname: Khanlou
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Braun
authors.affiliation: Department of Radiological Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Ruchalski
authors.affiliation: Department of Medicine, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.
authors.forename: Heike
authors.initials: H
authors.lastname: Seifert
authors.affiliation: Department of Medicine, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Dahlman
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Alain
authors.initials: A
authors.lastname: Algazi
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: rlo@mednet.ucla.edu.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf