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Clin Cancer Res. 2018 Mar 15;24(6):1426-1435. doi: 10.1158/1078-0432.CCR-17-2141. Epub 2017 Dec 28.

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

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Department of Medicine, Vanderbilt University, Nashville, Tennessee.
Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
Center for Structural Biology, Vanderbilt University, Nashville, Tennessee.
Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee.
Foundation Medicine, Inc., Cambridge, Massachusetts.
Guardant Health, Inc., Redwood, California.
Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
Meyer Cancer Center of Weill Cornell Medical College, New York, New York.
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.


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.

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