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Ref Type Journal Article
PMID (15647370)
Authors Kang S, Bader AG, Vogt PK
Title Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic.
Journal Proceedings of the National Academy of Sciences of the United States of America
Vol 102
Issue 3
Date 2005 Jan 18
URL
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.

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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 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
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