Abstract
AbstractBRAFV600Emutation occurs in 46% of melanomas and drives high levels of ERK activity and ERK-dependent proliferation. However, BRAFV600Eis insufficient to drive melanoma in GEMM models, and 82% of human benign nevi harborBRAFV600Emutations. We show here that BRAFV600Einhibits mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition leads to RAC1 activation and restores migration and invasion. In cells with BRAFV600E, activating RAC1 mutation, overexpression of PREX1, PREX2, or PTEN inactivation restore RAC1 activity and cell motility. Together, these lesions occur in 48% ofBRAFV600Emelanomas. Thus, although BRAFV600Eactivation 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.
Publisher
Cold Spring Harbor Laboratory