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|Ref Type||Journal Article|
|Authors||Kang S, Bader AG, Vogt PK|
|Title||Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic.|
|Abstract Text||Mutations in genes that encode components of the phosphatidyl-inositol 3-kinase (PI3-kinase) signaling pathway are common in human cancer. The recent discovery of nonrandom somatic mutations in the PIK3CA gene of many human tumors suggests an oncogenic role for the mutated enzyme. We have determined the growth-regulatory and signaling properties of the three most frequently observed PI3-kinase mutations: E542K, E545K, and H1047R. Expressed in chicken embryo fibroblasts, all three mutants induce oncogenic transformation with high efficiency. This transforming ability is correlated with elevated catalytic activity in in vitro kinase assays. The mutant-transformed cells show constitutive phosphorylation of Akt, of p70 S6 kinase, and of the 4E-binding protein 1. Phosphorylation of S6 kinase and of 4E-binding protein 1 is regulated by the target of rapamycin (TOR) kinase and affects rates of protein synthesis. The inhibitor of TOR, rapamycin, strongly interferes with cellular transformation induced by the PI3-kinase mutants, suggesting that the TOR and its downstream targets are essential components of the transformation process. The oncogenic transforming activity makes the mutated PI3-kinase proteins promising targets for small molecule inhibitors that could be developed into effective and highly specific anticancer drugs.|
|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|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA E545K||Advanced Solid Tumor||sensitive||Sirolimus||Preclinical||Actionable||In a preclinical study, Rapamune (sirolimus) demonstrated efficacy in inhibiting transformation of cultured cells containing PIK3CA E545K mutations (PMID: 15647370).||15647370|
|PIK3CA H1047R||Advanced Solid Tumor||sensitive||Sirolimus||Preclinical||Actionable||In a preclinical study, transformed cells expressing PIK3CA H1047R were sensitive to Rapamune (sirolimus), resulting in inhibition of transformation in culture (PMID: 15647370).||15647370|
|PIK3CA E542K||Advanced Solid Tumor||sensitive||Sirolimus||Preclinical||Actionable||In a preclinical study, Rapamune (sirolimus) demonstrated efficacy in inhibiting transformation of cultured cells containing PIK3CA E542K mutations (PMID: 15647370).||15647370|