Identification of NRAS isoform 2 over-expression as a novel mechanism facilitating BRAF inhibitor resistance in malignant melanoma

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Date

2017-03

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Research Projects

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Abstract

Activating mutations in BRAF are found in 50% of melanomas and although treatment with BRAF inhibitors (BRAFi) is effective, resistance often develops. We now show that recently discovered NRAS isoform-2 is up-regulated in the setting of BRAF inhibitor resistance in melanoma, in both cell lines and patient tumor tissues. When isoform-2 was over-expressed in BRAF mutant melanoma cell lines, melanoma cell proliferation and in vivo tumor growth were significantly increased in the presence of BRAFi treatment. shRNA-mediated knockdown of isoform-2 in BRAFi resistant cells restored sensitivity to BRAFi compared to controls. Signaling analysis indicated decreased mitogen-activated protein kinase (MAPK) pathway signaling and increased phosphoinositol-3-kinase (PI3K) pathway signaling in isoform- 2 overexpressing cells compared to isoform-1 overexpressing cells. Immunoprecipitation of isoform-2 validated a binding affinity of this isoform to both PI3K and BRAF/RAF1. The addition of an AKT inhibitor to BRAFi treatment resulted in a partial restoration of BRAFi sensitivity in cells expressing high levels of isoform-2. NRAS isoform-2 may contribute to resistance to BRAFi by facilitating PI3K pathway activation.

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Professional Biological Sciences: 3rd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)

Keywords

Melanoma, NRAS, BRAF, drug resistance

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