The farnesyl transferase inhibitor darlifarnib (KO-2806) re-sensitizes relapsing tumors to RAS inhibition

Resistance remains a key issue limiting the clinical benefit from RAS-targeting therapeutic agents and necessitates combination approaches. Here, we identified persistent mTORC1 activity in preclinical KRAS-mutant non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models as a frequent, nongenetic driver of inherent and adaptive resistance to RAS inhibition. This vulnerability was targetable with the farnesyl transferase inhibitor darlifarnib (KO-2806), which blocks mTORC1 activation via RHEB while sparing mTORC2 to limit associated toxicities. The addition of KO-2806 to NSCLC or CRC tumors progressing on mutant-selective RAS inhibitors led to rapid and durable tumor regression. In contrast, switching from mutant-selective to pan-RAS inhibitor monotherapy resulted in only stasis of NSCLC tumors and had no effect on CRC tumor progression. Further, the addition of KO-2806 rescued sensitivity of progressing tumors to the pan-RAS inhibitor RMC-6236. These results establish mTORC1 as an important mediator of escape from RAS inhibition and highlight KO-2806 as a promising RAS companion inhibitor in patients with prior RAS inhibitor exposure.