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|Ref Type||Journal Article|
|Authors||Croessmann S, Sheehan JH, Lee KM, Sliwoski G, He J, Nagy R, Riddle D, Mayer IA, Balko JM, Lanman R, Miller VA, Cantley LC, Meiler J, Arteaga CL|
|Title||PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3Kα Inhibitors.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2018 03 15|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|PIK3CA||H450_P458del||deletion||gain of function||PIK3CA H450_P458del results in the deletion of nine amino acids in the C2 PI3K-type domain of the Pik3ca protein from amino acids 450 to 458 (UniProt.org). H450_P458del confers a gain of function to the Pik3ca protein as demonstrated by transformation in culture and activation of the PI3K/Akt/Mtor pathway via increased phosphorylation of Akt, Erk, P70S6K, and P90RSK (PMID: 29284706).|
|PIK3CA||P447_L455del||deletion||gain of function||PIK3CA P447_L455del results in the deletion of nine amino acids in the C2 PI3K-type domain of the Pik3ca protein from amino acids 447 to 455 (UniProt.org). P447_L455del confers a gain of function to the Pik3ca protein as demonstrated by transformation in culture and activation of the PI3K/Akt/Mtor pathway via increased phosphorylation of Akt, Erk, P70S6K, and P90RSK (PMID: 21266528, PMID: 29284706).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA P447_L455del||estrogen-receptor positive breast cancer||predicted - sensitive||Alpelisib + Letrozole||Case Reports/Case Series||Actionable||In a clinical case study, a patient with estrogen-receptor positive breast cancer harboring PIK3CA P447_L455del demonstrated an 11 month sustained response to the combination therapy of Femara (letrozole) and Alpelisib (BYL719) (PMID: 29284706).||29284706|
|PIK3CA H450_P458del||breast cancer||sensitive||Alpelisib||Preclinical - Cell culture||Actionable||In a preclinical study, transformed breast epithelial cells expressing PIK3CA H450_P458del were sensitive to treatment with Alpelisib (BYL719) in culture, demonstrating growth inhibition and decreased invasiveness of acini (PMID: 29284706).||29284706|