PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, 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 p110α E545K, but not p110α H1047R, gains the ability to associate with IRS1 independent of the p85 regulatory subunit, thereby rewiring this oncogenic signaling pathway. Disruption of the IRS1-p110α E545K interaction destabilizes the p110α protein, reduces AKT phosphorylation, and slows xenograft tumor growth of a cancer cell line expressing p110α E545K. Moreover, a hydrocarbon-stapled peptide that disrupts this interaction inhibits the growth of tumors expressing p110α E545K. ► p110α E545K helical domain mutant protein directly interacts with IRS1 ► IRS1-p110α E545K interaction stabilizes p110α E545K and brings it to the membrane ► IRS1 mutants that do not interact with p110α E545K reduce oncogenicity ► A peptide that disrupts IRS1-p110α E545K interaction inhibits tumor growth in vivo