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

Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.

Author information

1
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.
2
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
3
Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
4
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.
5
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.

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.

PMID:
26359985
PMCID:
PMC4821508
DOI:
10.1016/j.cell.2015.07.061
[Indexed for MEDLINE]
Free PMC Article

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