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Updated: Jun 28, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Tumorigenesis driven by the BRAFV600E oncoprotein requires secondary mutations that overcome its feedback inhibition
Sunyana Gadal1, Jacob A Boyer2, Simon F Roy3,4
1Molecular Pharmacology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
Abstract:
BRAF mutation occurs in 46% of melanomas and drives high levels of ERK activity and ERK-dependent proliferation. However, BRAF is insufficient to drive melanoma in GEMM models, and 82% of human benign nevi harbor BRAF mutations. We show here that BRAFV600E inhibits mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition induces RAC1 activation and restores migration and invasion. In cells with BRAF, mutant RAC1, overexpression of PREX1, PREX2, or PTEN inactivation restore RAC1 activity and cell motility. Together, these lesions occur in 48% of BRAFV600E melanomas. Thus, although BRAFV600E activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of cell migration. Secondary mutations are, therefore, required for tumorigenesis. One mechanism underlying tumor evolution may be the selection of lesions that rescue the deleterious effects of oncogenic drivers.
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