Abstract
<div>Abstract<p><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.</p><p><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.</p><p><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.</p><p><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>.</p></div>
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
