PIK3CA C-terminal frameshift mutations are novel oncogenic events that sensitize tumors to PI3K-α inhibition

Significance While PIK3CA hotspot mutations frequently occur in solid cancers and in some contexts are therapeutically actionable, numerous other PIK3CA genomic alterations have been observed but remain uncharacterized. The authors identify C-terminal PIK3CA frameshift mutations as oncogenic driver events dependent on p85 binding in breast cancer and other cancers. Breast cell lines and tumors expressing PIK3CA frameshift mutations are sensitive to PI3K inhibition via alpelisib treatment. Patients with tumors characterized by these mutations may derive clinical benefit from p110α-selective inhibition.