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

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

Cell

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:

Published: September 2015

AI Article Synopsis

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821508PMC
http://dx.doi.org/10.1016/j.cell.2015.07.061DOI Listing

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