PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3Kα Inhibitors.

ABSTRACT: 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 PIK3CA^delP447-L455 in complex with the p85 regulatory subunit and MCF10A cells expressing PIK3CA^delP447-L455 and PIK3CA^H450_P458del were used to understand the phenotype of C2 domain deletions.Results: Computational modeling revealed specific favorable inter-residue c

SUBMITTER: Croessmann S 

PROVIDER: S-EPMC5856622 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature