Therapeutic inhibition of RAS in non-small cell lung cancer.

Oncogenic KRAS mutations are the most common driver event in NSCLC, occurring in up to 30% of patients. Direct strategies to target KRAS (and other RAS isoforms) met with consistent failure until the discovery of covalent KRAS G12C inhibitors, leading to a first-in-class FDA accelerated approval for the treatment of NSCLC in 2021. Since then, multiple chemotypes have been reported to extend direct KRAS targeting beyond G12C alleles, with several dozen molecules entering early or late clinical testing in rapid succession. Here, we review such strategies. We recap the chemistry and clinical strategy behind G12C inhibitors as a first step in direct KRAS targeting. We then propose an overarching classification schema for novel KRAS targeting molecules, focusing on the chemical strategies encoded in their use, and moving beyond conventional inhibitors to glues, degraders, and other novel pharmacologies. We evaluate the non-G12C, allele-specific molecules (such as those targeting G12D), inhibitors of multiple KRAS alleles ("pan-KRAS") and inhibitors of all RAS isoforms ("pan-RAS"). We consider these molecules' potential as monotherapy, in combination with one another, and in combination with conventional (FDA-approved) or novel (unapproved) treatments. Finally, we discuss what the future may hold for KRAS directed strategies in NSCLC.