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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.

Author information

1
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
2
Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
3
Center for Structural Biology, Vanderbilt University, Nashville, Tennessee.
4
Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee.
5
Foundation Medicine, Inc., Cambridge, Massachusetts.
6
Guardant Health, Inc., Redwood, California.
7
Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
8
Meyer Cancer Center of Weill Cornell Medical College, New York, New York.
9
Department of Medicine, Vanderbilt University, Nashville, Tennessee. carlos.arteaga@utsouthwestern.edu.
10
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.

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 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.

PMID:
29284706
PMCID:
PMC5856622
[Available on 2019-03-15]
DOI:
10.1158/1078-0432.CCR-17-2141

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