Gain of Interaction with IRS1 by p110α-Helical Domain Mutants Is Crucial for Their Oncogenic Functions

PIK3CA, which encodes the p110 alpha catalytic subunit of phosphatidylinositol 3-kinase alpha, is frequently mutated in human cancers. Most of these mutations occur at two hot-spots: E545K and H1047R located in the helical domain and the kinase domain, respectively. Here, we report that p110 alpha E545K, but not p110 alpha H1047R, gains the ability to associate with IRS1 independent of the p85 regulatory subunit, thereby rewiring this oncogenic signaling pathway. Disruption of the IRS1-p110 alpha E545K interaction destabilizes the p110 alpha protein, reduces AKT phosphorylation, and slows xenograft tumor growth of a cancer cell line expressing p110 alpha E545K. Moreover, a hydrocarbon-stapled peptide that disrupts this interaction inhibits the growth of tumors expressing p110 alpha E545K.