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Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.
Hugo, Willy; Shi, Hubing; Sun, Lu; Piva, Marco; Song, Chunying; Kong, Xiangju; Moriceau, Gatien; Hong, Aayoung; Dahlman, Kimberly B; Johnson, Douglas B; Sosman, Jeffrey A; Ribas, Antoni; Lo, Roger S.
Affiliation
  • Hugo W; 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.
  • Shi H; 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.
  • Sun L; 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.
  • Piva M; 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.
  • Song C; 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.
  • Kong X; 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.
  • Moriceau G; 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.
  • Hong A; 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.
  • Dahlman KB; Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
  • Johnson DB; Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
  • Sosman JA; Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
  • Ribas A; 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
  • Lo RS; 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 Califo
Cell ; 162(6): 1271-85, 2015 Sep 10.
Article in En | MEDLINE | ID: mdl-26359985
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Drug Resistance, Neoplasm / MAP Kinase Signaling System / Melanoma Type of study: Prognostic_studies Limits: Humans Language: En Journal: Cell Year: 2015 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Drug Resistance, Neoplasm / MAP Kinase Signaling System / Melanoma Type of study: Prognostic_studies Limits: Humans Language: En Journal: Cell Year: 2015 Document type: Article Affiliation country: United States