Inverted chimeric RNAi molecules synergistically cotarget MYC and KRAS in KRAS-driven cancers.

ABSTRACT: Mutant KRAS has been implicated in driving a quarter of all cancer types. Although inhibition of the KRASG12C mutant protein has shown clinical promise, there is still a need for therapies that overcome resistance and target non-KRASG12C mutations. KRAS activates downstream MYC, which is also a difficult-to-drug oncoprotein. We have developed an "inverted" RNAi molecule with the passenger strand of a MYC-targeting siRNA fused to the guide strand of a KRAS-targeting siRNA. The chimeric molecule simultaneously inhibits KRAS and MYC, showing marked improvements in efficacy beyond the individual siRNA components. This effect is mediated by 5'-dT overhangs following endosomal metabolism. The synergistic RNAi activity led to a more than 10- to 40-fold improvement in inhibition of cancer viabilit

SUBMITTER: Chareddy YS 

PROVIDER: S-EPMC12483557 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature