Activating KRAS , NRAS , and BRAF mutants enhance proteasome capacity and reduce endoplasmic reticulum stress in multiple myeloma

Significance KRAS , NRAS , and BRAF mutations that activate MAPK signaling occur in half of myeloma patients and confer a poor prognosis. Our studies link activating RAS and RAF mutations with enhanced proteasome assembly and capacity through the MAPK intermediate ELK1. These downstream changes reduce cellular stress, thereby promoting myeloma cell survival, and confer proteasome inhibitor resistance, which can be overcome by combinations with BRAF or MEK inhibitors. They provide a possible reason for the frequency of MAPK pathway mutations in myeloma, and support use of these combinations specifically in patients with BRAF - or RAS -mutated disease.