Purpose: We describe herein a novel P447_L455 deletion in the C2 domain of 
PIK3CA in a patient with an ER+ breast cancer with an excellent response to the 
PI3Kα inhibitor alpelisib. Although PIK3CA deletions are relatively rare, a 
significant portion of deletions cluster within amino acids 446-460 of the C2 
domain, suggesting these residues are critical for p110α function.Experimental 
Design: A computational structural model of PIK3CAdelP447-L455 in complex with 
the p85 regulatory subunit and MCF10A cells expressing PIK3CAdelP447-L455 and 
PIK3CAH450_P458del were used to understand the phenotype of C2 domain 
deletions.Results: Computational modeling revealed specific favorable 
inter-residue contacts that would be lost as a result of the deletion, 
predicting a significant decrease in binding energy. Coimmunoprecipitation 
experiments showed reduced binding of the C2 deletion mutants with p85 compared 
with wild-type p110α. The MCF10A cells expressing PIK3CA C2 deletions exhibited 
growth factor-independent growth, an invasive phenotype, and higher 
phosphorylation of AKT, ERK, and S6 compared with parental MCF10A cells. All 
these changes were ablated by alpelisib treatment.Conclusions: C2 domain 
deletions in PIK3CA generate PI3K dependence and should be considered biomarkers 
of sensitivity to PI3K inhibitors. Clin Cancer Res; 24(6); 1426-35. ©2017 AACR.