title: Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.
abstract: Clinically acquired resistance to MAPK inhibitor (MAPKi) therapies for melanoma cannot be fully explained by genomic mechanisms and may be accompanied by co-evolution of intra-tumoral immunity. We sought to discover non-genomic mechanisms of acquired resistance and dynamic immune compositions by a comparative, transcriptomic-methylomic analysis of patient-matched melanoma tumors biopsied before therapy and during disease progression. Transcriptomic alterations across resistant tumors were highly recurrent, in contrast to mutations, and were frequently correlated with differential methylation of tumor cell-intrinsic CpG sites. We identified in the tumor cell compartment supra-physiologic c-MET up-expression, infra-physiologic LEF1 down-expression and YAP1 signature enrichment as drivers of acquired resistance. Importantly, high intra-tumoral cytolytic T cell inflammation prior to MAPKi therapy preceded CD8 T cell deficiency/exhaustion and loss of antigen presentation in half of disease-progressive melanomas, suggesting cross-resistance to salvage anti-PD-1/PD-L1 immunotherapy. Thus, melanoma acquires MAPKi resistance with highly dynamic and recurrent non-genomic alterations and co-evolving intra-tumoral immunity.
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, 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 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, 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 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Piva
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Song
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, 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 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, 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 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA.
authors.forename: Aayoung
authors.initials: A
authors.lastname: Hong
authors.affiliation: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Dahlman
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, 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 90095-1662, USA; Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA; Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, 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 90095-1662, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA. Electronic address: rlo@mednet.ucla.edu.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D010750:Phosphoproteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D051176:beta Catenin; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases