Components of the phosphatidylserine endoplasmic reticulum to plasma membrane transport mechanism as targets for KRAS inhibition in pancreatic cancer

Abstract

Significance Exquisite lipid-binding specificity for phosphatidylserine (PtdSer) is hardwired into the structure of the KRAS C-terminal plasma membrane (PM) anchor. This renders KRAS–PM localization and hence biological function potentially vulnerable to perturbations of PM PtdSer content. Here, we show that all components of the recently described lipid transport machinery that maintain PM PtdSer content are indeed required to support KRAS oncogenic function. In this context, we demonstrate that the enzyme, PI4KIIIα, in particular has merit as a druggable target for inhibiting KRAS -dependent tumors. More generally, we provide insight into how PM phospholipids can regulate oncogene signaling and how PM lipid composition may be successfully targeted to exploit tumor vulnerabilities.