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

hotspot mutation is well established as an oncogenic driver event in cancer and its durable and efficacious inhibition is a focus in the development and testing of clinical cancer therapeutics. However, hundreds of cancer-associated mutations remain uncharacterized, their sensitivity to PI3K inhibitors unknown. Here, we describe a series of C-terminal mutations, primarily nucleotide insertions, that produce a frame-shifted protein product with an extended C terminus.