Unknown

Dataset Information

0

PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3K? 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 PI3K? 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 p110? 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 p110?. 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.

SUBMITTER: Croessmann S 

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

REPOSITORIES: biostudies-literature

altmetric image

Publications

<i>PIK3CA</i> C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3K<b>α</b> Inhibitors.

Croessmann Sarah S   Sheehan Jonathan H JH   Lee Kyung-Min KM   Sliwoski Gregory G   He Jie J   Nagy Rebecca R   Riddle David D   Mayer Ingrid A IA   Balko Justin M JM   Lanman Richard R   Miller Vincent A VA   Cantley Lewis C LC   Meiler Jens J   Arteaga Carlos L CL  

Clinical cancer research : an official journal of the American Association for Cancer Research 20171228 6


<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-L45  ...[more]

Similar Datasets

| S-EPMC3712624 | biostudies-literature
| S-EPMC2614767 | biostudies-literature
| S-EPMC1413824 | biostudies-literature
| S-EPMC6321576 | biostudies-literature
| S-EPMC3940863 | biostudies-literature
| S-EPMC3478612 | biostudies-literature
| S-EPMC8137641 | biostudies-literature
| S-EPMC10543974 | biostudies-literature
| S-EPMC3391087 | biostudies-literature
| S-EPMC4814170 | biostudies-literature