Reference Detail

Ref Type

Journal Article

PMID

(21673091)

Authors

Bhagwat SV, Gokhale PC, Crew AP, Cooke A, Yao Y, Mantis C, Kahler J, Workman J, Bittner M, Dudkin L, Epstein DM, Gibson NW, Wild R, Arnold LD, Houghton PJ, Pachter JA

Title

Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	10	8	2011 Aug	1394-406	Mol Cancer Ther

URL

Abstract Text

The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is frequently activated in human cancers, and mTOR is a clinically validated target. mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, metabolism, proliferation, and survival. Rapamycin and its analogues partially inhibit mTOR through allosteric binding to mTORC1, but not mTORC2, and have shown clinical utility in certain cancers. Here, we report the preclinical characterization of OSI-027, a selective and potent dual inhibitor of mTORC1 and mTORC2 with biochemical IC(50) values of 22 nmol/L and 65 nmol/L, respectively. OSI-027 shows more than 100-fold selectivity for mTOR relative to PI3Kα, PI3Kβ, PI3Kγ, and DNA-PK. OSI-027 inhibits phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1 as well as the mTORC2 substrate AKT in diverse cancer models in vitro and in vivo. OSI-027 and OXA-01 (close analogue of OSI-027) potently inhibit proliferation of several rapamycin-sensitive and -insensitive nonengineered and engineered cancer cell lines and also, induce cell death in tumor cell lines with activated PI3K-AKT signaling. OSI-027 shows concentration-dependent pharmacodynamic effects on phosphorylation of 4E-BP1 and AKT in tumor tissue with resulting tumor growth inhibition. OSI-027 shows robust antitumor activity in several different human xenograft models representing various histologies. Furthermore, in COLO 205 and GEO colon cancer xenograft models, OSI-027 shows superior efficacy compared with rapamycin. Our results further support the important role of mTOR as a driver of tumor growth and establish OSI-027 as a potent anticancer agent. OSI-027 is currently in phase I clinical trials in cancer patients.

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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
PTEN loss	breast cancer	sensitive	OSI-027	Preclinical - Cell line xenograft	Actionable	In a preclinical study, OSI-027 induced tumor regression in PTEN-null breast cancer cell line xenograft models (PMID: 21673091).	21673091
PTEN loss	ovarian cancer	sensitive	OSI-027	Preclinical - Cell line xenograft	Actionable	In a preclinical study, OSI-027 inhibited tumor growth in PTEN-null ovarian cancer cell line xenograft models (PMID: 21673091).	21673091
PIK3CA mutant	ovarian cancer	sensitive	OSI-027	Preclinical - Cell line xenograft	Actionable	In a preclinical study, OSI-027 inhibited tumor growth in ovarian cancer cell line xenograft models harboring PIK3CA mutations (PMID: 21673091).	21673091
PIK3CA mutant	breast cancer	sensitive	OSI-027	Preclinical - Cell line xenograft	Actionable	In a preclinical study, OSI-027 induced tumor regression in breast cancer cell line xenograft models harboring PIK3CA mutations (PMID: 21673091).	21673091