Data from Tumorigenesis Driven by BRAF^V600E Requires Secondary Mutations That Overcome Its Feedback Inhibition of RAC1 and Migration

BRAF^V600E mutations occur in 46% of melanomas and drive high levels of ERK activity and ERK-dependent proliferation. However, BRAF^V600E is insufficient to drive melanoma in genetically engineered mouse models, and 82% of human benign nevi harbor BRAF^V600E mutations. We found that BRAF^V600E inhibited mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition induced RAC1 activation and restored migration and invasion. In cells with BRAF^V600E, mutant RAC1 or PTEN inactivation restored RAC1 activity and cell motility. Together, these lesions occurred in 26% of melanomas with BRAF^V600E mutations. Thus, although BRAF^V600E activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of RAC1. 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.

Significance: Secondary genetic lesions that rescue BRAF^V600E/ERK-induced feedback inhibition on cell migration are required for tumorigenesis, indicating that oncogenic feedback may shape the genetic landscape and select for mutations that are therapeutic targets.