p85β regulates autophagic degradation of AXL to activate oncogenic signaling

PIK3R2 encodes the p85 beta regulatory subunit of phosphatidylinositol 3-kinase and is frequently amplified in cancers. The signaling mechanism and therapeutic implication of p85 beta are poorly understood. Here we report that p85 beta upregulates the protein level of the receptor tyrosine kinase AXL to induce oncogenic signaling in ovarian cancer. p85 beta activates p110 activity and AKT-independent PDK1/SGK3 signaling to promote tumorigenic phenotypes, which are all abolished upon inhibition of AXL. At the molecular level, p85 beta alters the phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate the selective regulation of AXL by p85 beta, thereby disrupting the autophagic degradation of the AXL protein. Therapeutically, p85 beta expression renders ovarian cancer cells vulnerable to inhibitors of AXL, p110, or PDK1. Conversely, p85 beta -depleted cells are less sensitive to these inhibitors. Together, our findings provide a rationale for pharmacological blockade of the AXL signaling axis in PIK3R2-amplified ovarian cancer. p85 beta (PIK3R2), a regulatory subunit of PI3K, has oncogenic properties. Here the authors show that p85 beta promotes AXL protein stability, which in turn activates p110 to induce PDK1/SGK3 signaling, and therapeutically, p85 beta -expressing ovarian cancer cells are sensitive to AXL inhibition.