An Antagonist of KSR1-Driven Adaptive Resistance to Clinical RAS-MAPK Inhibitors.

Kinase Suppressor of RAS (KSR), RAF and MEK function downstream of RAS and upstream of ERK to mediate growth factor and receptor tyrosine kinase (RTK) signaling. Significant clinical breakthroughs have occurred in targeting mutant oncogenes and vulnerabilities in the RAS-MAPK pathway, including against KRAS-G12C, BRAF-V600E, and MEK1/2. However, these drugs have revealed that the inhibition of individual RAS-MAPK signaling molecules can lead to relief of negative feedback signaling and paradoxically amplify RAS-MAPK output over time. Indeed this mechanism, sometimes referred to as 'rebound signaling', has arose as a key driver of adaptive drug resistance to several classes of therapies. We hypothesize that KSR1, an isoform implicated in several Ras-driven cancers, may function in the resistance mechanisms to Ras-MAPK inhibition therapy. To test this hypothesis, we evaluate KSR1 as a driver of resistance to RAS-MAPK inhibition and developed a selective KSR1 antagonist, K-X1. We discovered strong synergy between K-X1 and MEK inhibition in models of adaptive resistance. In vivo target engagement assays suggest that K-X1 operates through alterations in the stability and interactions of KSR1-mediated complexes. Our work highlights a potential strategy to overcome adaptive resistance to therapies targeting the MAPK pathway via KSR1.