RAS Mutation-Specific Responses to Paralog- and State-Selective RAS Inhibitors.

ABSTRACT: A high therapeutic index, defined as potent inhibition of oncogenic signaling in tumor cells with minimal effects on normal cells, is critical for effective cancer therapies. Recent advances have introduced diverse RAS-targeting inhibitors, including mutant-specific inhibitors such as KRAS G12C and KRAS G12D, as well as paralog- and state-selective inhibitors. Non-mutant-specific RAS inhibition can be achieved by: (i) guanine nucleotide exchange-OFF inhibitors that indirectly inactivate RAS by targeting SHP2 or SOS1, (ii) KRAS-OFF inhibitors that spare NRAS and HRAS, and (iii) active-state RAS(ON) inhibitors that directly block binding of effector RAF. However, the signaling inhibition index (SII)-the differential suppression of oncogenic signaling between RAS-mutant and normal cells-remai

SUBMITTER: Baars B 

PROVIDER: S-EPMC12710464 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature