Targeting the Protein-Protein Interaction between IRS1 and Mutant p110 alpha for Cancer Therapy

Phosphoinositide-3-kinase, catalytic, alpha polypeptide, which encodes the catalytic p110 alpha subunit of phosphatidylinositol 3-kinase alpha, is the most frequently mutated oncogene in human cancers. Targeting mutant p110 alpha holds great promise for cancer therapy. However, it is challenging to develop p110 alpha isoform-specific inhibitors. Most p110 alpha mutations occur at two hot spot regions: an acidic cluster (E542, E545, and Q546) in the helical domain and a histidine residue (H1047) in the kinase domain. We recently discovered that p110 alpha helical domain mutant proteins, but not the kinase domain mutant proteins, directly associate with insulin receptor substrate 1 (IRS1). Moreover, we demonstrated that disruption of protein-protein interaction between p110 alpha helical domain mutant and IRS1 inhibits the growth of tumors with such mutations. The direct protein interaction between IRS1 and p110 alpha helical domain mutants may provide a more accessible target for developing novel precision cancer therapy.