Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance

Cell. 2015 Sep 10;162(6):1271-85. doi: 10.1016/j.cell.2015.07.061.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis
  • CD8-Positive T-Lymphocytes / immunology
  • DNA Methylation
  • Drug Resistance, Neoplasm*
  • Gene Expression Profiling
  • Humans
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Melanoma / drug therapy*
  • Melanoma / genetics*
  • Melanoma / immunology
  • Phosphoproteins / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Transcription Factors
  • beta Catenin / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • Phosphoproteins
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • beta Catenin
  • RON protein
  • Receptor Protein-Tyrosine Kinases

Associated data

  • GEO/GSE65186