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|Ref Type||Journal Article|
|Authors||Madsen RR, Knox RG, Pearce W, Lopez S, Mahler-Araujo B, McGranahan N, Vanhaesebroeck B, Semple RK|
|Title||Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner.|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Date||2019 Apr 23|
|Abstract Text||The PIK3CA gene, which encodes the p110α catalytic subunit of PI3 kinase (PI3K), is mutationally activated in cancer and in overgrowth disorders known as PIK3CA-related overgrowth spectrum (PROS). To determine the consequences of genetic PIK3CA activation in a developmental context of relevance to both PROS and cancer, we engineered isogenic human induced pluripotent stem cells (iPSCs) with heterozygous or homozygous knockin of PIK3CAH1047R While heterozygous iPSCs remained largely similar to wild-type cells, homozygosity for PIK3CAH1047R caused widespread, cancer-like transcriptional remodeling, partial loss of epithelial morphology, up-regulation of stemness markers, and impaired differentiation to all three germ layers in vitro and in vivo. Genetic analysis of PIK3CA-associated cancers revealed that 64% had multiple oncogenic PIK3CA copies (39%) or additional PI3K signaling pathway-activating "hits" (25%). This contrasts with the prevailing view that PIK3CA mutations occur heterozygously in cancer. Our findings suggest that a PI3K activity threshold determines pathological consequences of oncogenic PIK3CA activation and provide insight into the specific role of this pathway in human pluripotent stem cells.|
|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||E418K||missense||unknown||PIK3CA E418K lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). E418K has been identified in the scientific literature (PMID: 30948643, PMID: 29615459, PMID: 25344691), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Sep 2020).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA H1047R||Advanced Solid Tumor||predicted - sensitive||Alpelisib||Preclinical - Cell culture||Actionable||In a preclinical study, Piqray (Alpelisib) decreased Akt phosphorylation and inhibited PI3K signaling, and demonstrated dose-dependent inhibition of survival in human pluripotent stem cells harboring PIK3CA H1047R in culture (PMID: 30948643).||30948643|