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

Christoph Krisp, Robert Parker, Dana Pascovici, Nicholas K. Hayward, James S. Wilmott, John F. Thompson, Graham J. Mann, Georgina V. Long, Richard A. Scolyer, Mark P. Molloy

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages713–723
Number of pages11
JournalBritish Journal of Cancer
Volume119
Issue number6
DOIs
Publication statusPublished - 17 Aug 2018

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Mitogen-Activated Protein Kinase Kinases
Proteomics
Melanoma
Proteins
Biomarkers
Cell Line
Messenger RNA
Survival
Intercellular Adhesion Molecule-1
Cell Adhesion
Cell Movement
Mass Spectrometry
Lymph Nodes
Genotype
Gene Expression
Skin
Pharmaceutical Preparations

Cite this

Krisp, Christoph ; Parker, Robert ; Pascovici, Dana ; Hayward, Nicholas K. ; Wilmott, James S. ; Thompson, John F. ; Mann, Graham J. ; Long, Georgina V. ; Scolyer, Richard A. ; Molloy, Mark P. / Proteomic phenotyping of metastatic melanoma reveals putative signatures of MEK inhibitor response and prognosis. In: British Journal of Cancer. 2018 ; Vol. 119, No. 6. pp. 713–723.
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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 na{\"i}ve 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.",
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Proteomic phenotyping of metastatic melanoma reveals putative signatures of MEK inhibitor response and prognosis. / Krisp, Christoph; Parker, Robert; Pascovici, Dana; Hayward, Nicholas K.; Wilmott, James S.; Thompson, John F.; Mann, Graham J.; Long, Georgina V.; Scolyer, Richard A.; Molloy, Mark P.

In: British Journal of Cancer, Vol. 119, No. 6, 17.08.2018, p. 713–723.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Proteomic phenotyping of metastatic melanoma reveals putative signatures of MEK inhibitor response and prognosis

AU - Krisp,Christoph

AU - Parker,Robert

AU - Pascovici,Dana

AU - Hayward,Nicholas K.

AU - Wilmott,James S.

AU - Thompson,John F.

AU - Mann,Graham J.

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AU - Scolyer,Richard A.

AU - Molloy,Mark P.

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N2 - 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.

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