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PKC-alpha regulates the phosphorylation of KRAS that suppresses its oncogenic properties

KRAS-calmodulin (CaM) signaling axis reportedly regulates the oncogenic properties of KRAS. Phosphorylation of KRAS by PKC uncouples KRAS-CaM and consequently suppresses KRAS-driven malignancies. However, broadly activating PKC could mediate tumor promoting signaling nodes and cause systemic toxicity, diming its applicability as an anti-KRAS therapy. Here, we found that prostratin, but not byrostatin, specifically mediates KRAS phosphorylation, resulting in an elevated level of active CaM in the cytosol and suppresses malignancies of KRAS mutant cells. A whole-genome wide CRISPR/Cas9 knockout screening followed by biochemistry approaches revealed that prostratin acts through activating PKCα. Functional studies confirmed PKCα as the key kinase to phosphorylate KRAS and, therefore, a KRAS suppressor. Activated PKCα induced senescence in KRAS mutant tumor cells through PTPN14, accompanied by a secretory phenotype contributing to the growth inhibition. Our findings reveal a previously understudied regulation of KRAS-CaM axis by PKCα, which can be an actionable target for developing anti-KRAS therapeutics.