Reference Detail

Ref Type

Journal Article

PMID

(29245078)

Authors

Yan J, Wu X, Yu J, Yu H, Xu T, Brown KM, Bai X, Dai J, Ma M, Tang H, Si L, Chi Z, Sheng X, Cui C, Kong Y, Guo J

Title

Analysis of NRAS gain in 657 patients with melanoma and evaluation of its sensitivity to a MEK inhibitor.

Journal	Vol	Issue	Date	Pages	Journal Short Title
European journal of cancer (Oxford, England : 1990)	89		2018 01	90-101	Eur J Cancer

URL

Abstract Text

Neuroblastoma rat-sarcoma (NRAS) mutations have been described in Chinese patients with melanoma. However, the status and the clinical significance of NRAS gain have not been investigated on a large scale.A total of 657 melanoma samples were included in the study. NRAS copy number was examined using the QuantiGene Plex DNA assay. The sensitivities of cell lines and patient-derived xenograft (PDX) models containing NRAS gain to a MAP/ERK kinase (MEK) inhibitor (binimetinib) were also evaluated.The overall incidence of NRAS gain was 14.0% (92 of 657). Incidence of NRAS gain in acral, mucosal, chronic sun-induced damage (CSD) and non-CSD melanomas was 12.2%, 15.8%, 9.5% and 19.4%, respectively. NRAS gain was mutually exclusive to NRAS mutations (P = 0.036). The median survival time for melanoma patients with NRAS gain was significantly shorter than that for patients with normal NRAS copy number (P = 0.006). For patients containing NRAS gain, the median survival time for higher copy number (>4 copies) was significantly shorter than those with lower copy number (2-4 copies; P = 0.002). The MEK inhibitor (binimetinib) inhibited the proliferation of melanoma cells and the tumour growth of PDX models with NRAS gain.NRAS gain is frequent in patients with melanoma and may predict a poor prognosis of melanoma. The melanoma cells and PDX models containing NRAS gain are sensitive to MEK inhibitor (binimetinib), indicating that NRAS gain might be a new therapeutic target for melanoma.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS amp	melanoma	predicted - sensitive	Binimetinib	Preclinical - Pdx	Actionable	In a preclinical study, Mektovi (binimetinib) treatment resulted in reduced tumor growth and proliferation in two patient-derived xenograft (PDX) melanoma models with NRAS copy number gain and without BRAF or NRAS mutations (PMID: 29245078).	29245078
BRAF V600D NRAS dec exp	melanoma	no benefit	Binimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring BRAF V600D and knockdown of NRAS demonstrated a decreased response to Mektovi (binimetinib) relative to cells without NRAS knockdown in culture (PMID: 29245078).	29245078
NRAS over exp	melanoma	predicted - sensitive	Binimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mektovi (binimetinib) treatment in melanoma cell lines with NRAS overexpression, but without NRAS or BRAF mutations, resulted in reduced downstream signaling and proliferation in cultured cells (PMID: 29245078).	29245078