Proteomic phenotyping of metastatic melanoma reveals putative signatures of MEK inhibitor response and prognosis

Br J Cancer. 2018 Sep;119(6):713-723. doi: 10.1038/s41416-018-0227-2. Epub 2018 Aug 17.

Abstract

Background: Genotyping of melanomas is used to identify patients for treatment with BRAF and MEK inhibitors, but clinical responses are highly variable. This study investigated the utility of protein expression phenotyping to provide an integrated assessment of gene expression programs in BRAF/NRAS melanoma which would be useful for prognosis and may predict response to MEK inhibition.

Methods: Mass spectrometry profiling of early passage cell lines established from Stage III cutaneous melanomas was conducted. Basal protein expression was correlated with in vitro response to the MEK inhibitor, selumetinib. Protein expression in a cohort of 32 drug naïve BRAF/NRAS metastatic melanoma specimens was examined. The prognostic utility of a subset of these proteins and mRNA transcripts from a separate cohort was determined.

Results: Unsupervised analysis of basal cell line protein abundances delineated response to selumetinib, but BRAF/NRAS genotype did not. Resistance was associated with functions including cell motility, cell adhesion and cytoskeletal organization. Several of these response biomarkers were observed in lymph node biospecimens and correlated with melanoma-specific survival. Loss of ICAM-1 protein and mRNA expression was a strong prognosticator of diminished survival in BRAF/NRAS mutant melanoma.

Conclusions: These results demonstrate the utility of proteomic phenotyping to identify both putative biomarkers of response to MEK inhibition and prognostication associated with metastatic melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use*
  • Cell Line, Tumor
  • Chromatography, Liquid
  • Cohort Studies
  • Female
  • GTP Phosphohydrolases / genetics
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics*
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Male
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology
  • Membrane Proteins / genetics
  • Mutation*
  • Neoplasm Staging
  • Prognosis
  • Protein Kinase Inhibitors
  • Proteomics / methods*
  • Proto-Oncogene Proteins B-raf / genetics
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Survival Analysis
  • Tandem Mass Spectrometry

Substances

  • AZD 6244
  • Benzimidazoles
  • ICAM1 protein, human
  • Membrane Proteins
  • Protein Kinase Inhibitors
  • Intercellular Adhesion Molecule-1
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • GTP Phosphohydrolases
  • NRAS protein, human

Supplementary concepts

  • Melanoma, Cutaneous Malignant