Oncogenic BRAF Induces Whole-Genome Doubling Through Suppression of Cytokinesis

Abstract

Melanomas and other solid tumors commonly have increased ploidy, with near-tetraploid karyotypes being most frequently observed. Such karyotypes have been shown to arise through whole-genome doubling events that occur during early stages of tumor progression. The generation of tetraploid cells via whole-genome doubling is proposed to allow nascent tumor cells the ability to sample various protumorigenic genomic configurations while avoiding the negative consequences that chromosomal gains or losses have in diploid cells. Whereas a high prevalence of whole-genome doubling events has been established, the means by which whole-genome doubling arises is unclear. Here, we find that BRAFV600E, the most common mutation in melanomas, can induce whole-genome doubling via cytokinesis failure in vitro and in a zebrafish melanoma model. Mechanistically, BRAFV600E causes decreased activation and localization of RhoA, a critical cytokinesis regulator. BRAFV600E activity during G1/S phases of the cell cycle is required to suppress cytokinesis. During G1/S, BRAFV600E activity causes inappropriate centriole amplification, which is linked in part to inhibition of RhoA and suppression of cytokinesis. Together these data suggest that common abnormalities of melanomas linked to tumorigenesis – amplified centrosomes and whole-genome doubling events – can be induced by oncogenic BRAF and other mutations that increase RAS/MAPK pathway activity.

Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage

“…Indeed, activation of RAF/MEK/ERK pathway is observed in ~40% of tumors 71 and is the consequence of oncogenic mutations of different molecular players operating in this signaling cascade. Mutations in RAS and RAF genes -and of CRAF in particular -have been associated with high degree of CIN and aneuploidy 54,[72][73][74][75] , lending further support to the importance of this pathway for the cellular response to aneuploidy. Notably, RPE1 cells are KRAS-mutant, but our findings clearly indicate that the pathway does not reach its maximum activity in the parental population and is further activated following aneuploidy induction.…”

Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer harboring BRAF mutations

“…BRAF is a member of the RAF family of serine/threonine kinases and is part of the mitogen-activated protein kinase (MAPK) pathway, which is essential for regulating cell growth, proliferation and survival (29). In papillary thyroid cancers, colorectal cancers, and melanoma, BRAF mutations have been well documented, but not in NSCLCs, due to their low incidence.…”