Distinct ERK and PI3K dependencies mediate a heterogeneous response to RAS(ON) inhibition in KRAS-mutant colorectal cancer

RAS inhibitors have demonstrated limited efficacy in KRAS -mutant colorectal cancer (CRC). Here, we evaluate RMC-7977, a RAS(ON) multi-selective inhibitor, which shows a heterogeneous response in a panel of preclinical CRC models. Inhibition of PI3K signaling and cyclin D1 ( CCND1 ) expression are strongly correlated with response. We find that stratifying tumors based on the ERK dependence of cyclin D1, mediated by variability in CCND1 mRNA regulation, reveals two distinct resistance mechanisms. PI3K signaling plays a key role in driving persistent cyclin D1 expression in the less ERK-dependent tumors, and concurrent inhibition of RAS and PI3K can synergistically cause cell cycle arrest and promote apoptosis. However, in tumors with strongly ERK-dependent cyclin D1, vertical inhibition of RAS and MEK prevents feedback re-activation of the MAPK/ERK pathway and is more effective. In summary, we identify cyclin D1 as an important integrator and functional readout of upstream signaling that can inform optimal combination strategies for KRAS -mutant CRC.