Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	102	3	2005 Jan 18	802-7	Proc Natl Acad Sci U S A

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 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
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