<i>PIK3CA</i> C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3K<b>α</b> Inhibitors.
basic_science · Level V
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- Record sourced from PubMed, PMID 29284706.
- Also identified by DOI 10.1158/1078-0432.CCR-17-2141 and PMC identifier 5856622.
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Abstract
<b>Purpose:</b> We describe herein a novel P447_L455 deletion in the C2 domain of <i>PIK3CA</i> in a patient with an ER<sup>+</sup> breast cancer with an excellent response to the PI3Kα inhibitor alpelisib. Although <i>PIK3CA</i> 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.<b>Experimental Design:</b> A computational structural model of <i>PIK3CA</i><sup>delP447-L455</sup> in complex with the p85 regulatory subunit and MCF10A cells expressing <i>PIK3CA</i><sup>delP447-L455</sup> and <i>PIK3CA</i><sup>H450_P458del</sup> were used to understand the phenotype of C2 domain deletions.<b>Results:</b> 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 <i>PIK3CA</i> 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.<b>Conclusions:</b> C2 domain deletions in <i>PIK3CA</i> generate PI3K dependence and should be considered biomarkers of sensitivity to PI3K inhibitors. <i>Clin Cancer Res; 24(6); 1426-35. ©2017 AACR</i>.