The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human 
cancers. These mutations render RAS GTP-bound and active, constitutively binding 
effector proteins to promote signaling conducive to tumorigenic growth. To 
further elucidate how RAS oncoproteins signal, we mined RAS interactomes for 
potential vulnerabilities. Here we identify EFR3A, an adapter protein for the 
phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. 
Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, 
phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic 
signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma 
membrane. Finally, we show that a selective PI4KA inhibitor augments the 
antineoplastic activity of the KRASG12C inhibitor sotorasib, suggesting a 
clinical path to exploit this pathway. In sum, we have discovered a distinct 
KRAS signaling axis with actionable therapeutic potential for the treatment of 
KRAS-mutant cancers.