MEK1/2-Targeting PROTACs Promote the Collateral Degradation of CRAF in KRAS Mutant Cells

Abstract

SUMMARYActivation of the RAS/MAPK pathway is one of the most frequent alterations in cancer; yet therapies targeting this pathway have shown limited benefit due to drug resistance. For example, resistance to MEK inhibitors in KRAS mutant cancer cells occurs due to relief of a negative feedback that promotes CRAF activation and CRAF-MEK protein interactions, bypassing MEK inhibition. Consequently, combining CRAF and MEK inhibitors for KRAS mutant cancer is an area of intense research. Here, we discovered that the MEK1/2 PROTAC (Proteolysis-Targeting Chimeras) degrader, MS934, caused collateral degradation of CRAF in KRAS mutant cells via a PROTAC-mechanism, offering a new strategy to simultaneously degrade both CRAF and MEK1/2. Importantly, CRAF has been shown to have essential kinase-independent growth and survival functions outside the MEK-ERK pathway in KRAS mutant cells, making CRAF degradation an attractive therapeutic avenue. Despite this, to the best of our knowledge, no CRAF PROTACs have been published. Importantly, our discovery of MS934 as a first-in-class dual CRAF/MEK degrader provides a newfound approach to overcome MEK inhibitor resistance due to relief of negative feedback, as well as block CRAF kinase-independent functions in KRAS mutant cells.