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 Molecular cancer therapeutics
Vol 10
Issue 8
Date 2011 Aug
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
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 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
KRAS 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 KRAS mutations (PMID: 21673091). 21673091
Unknown unknown breast cancer not applicable OSI-027 Preclinical - Cell line xenograft Actionable In a preclinical study, OSI-027 inhibited mTORC1 and mTORC2 signaling and growth in breast cancer cells in culture and in cell line xenograft models (PMID: 21673091). 21673091
Unknown unknown colorectal cancer not applicable OSI-027 Preclinical - Cell line xenograft Actionable In a preclinical study, OSI-027 inhibited mTORC1 and mTORC2 signaling and growth in colorectal cancer cell line xenograft models (PMID: 21673091). 21673091
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