RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling.

ABSTRACT: Activating BRAF mutants and fusions signal as RAS-independent constitutively active dimers with the exception of BRAF V600 mutant alleles which can function as active monomers¹. Current RAF inhibitors are monomer selective, they potently inhibit BRAF V600 monomers but their inhibition of RAF dimers is limited by induction of negative cooperativity when bound to one site in the dimer^1-3. Moreover, acquired resistance to these drugs is usually due to molecular lesions that cause V600 mutants to dimerize^4-8. We show here that PLX8394, a new RAF inhibitor⁹, inhibits ERK signaling by specifically disrupting BRAF-containing dimers, including BRAF homodimers and BRAF-CRAF heterodimers, but not CRAF homodimers or ARAF-containing dimers. Differences in th

SUBMITTER: Yao Z 

PROVIDER: S-EPMC6404779 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature