Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin

Bhagwat, Shripad V.; Gokhale, Prafulla C.; Crew, Andrew P.; Cooke, Andy; Yao, Yan; Mantis, Christine; Kahler, Jennifer; Workman, Jennifer E.; Bittner, Mark; Dudkin, Lorina; Epstein, David; Gibson, Neil W.; Wild, Robert A.; Arnold, Lee D.; Houghton, Peter J.; Pachter, Jonathan A.

doi:10.1158/1535-7163.mct-10-1099

Cited by 181 publications

(168 citation statements)

References 31 publications

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“…S1C-S1D). This is consistent with other selective inhibitors of mTOR kinase (25), arguing that, although the mTOR pathway is important for cell growth, other pathways support survival. The lack of cell killing as a single-agent suggests that combination treatment, with standard of care agents or other targeted therapies, may be required to achieve cell death and tumor regression in patients with solid tumors.…”

Section: Discussionsupporting

confidence: 86%

CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

Mortensen¹,

Fultz²,

Xu³

et al. 2015

Molecular Cancer Therapeutics

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Section: Discussionsupporting

confidence: 86%

CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

Mortensen¹,

Fultz²,

Xu³

et al. 2015

Molecular Cancer Therapeutics

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“…Recent studies have characterized OSI-027 as a novel and potent mTOR kinase inhibitor that displays activity against both mTORC1 and mTORC2 [18][19][20]. In the current study, we found that targeting mTORC1/2 withOSI-027 inhibited the proliferation and migration of keloid keratinocytes, where mTOR was found to be overactivated.…”

Section: Introductionsupporting

confidence: 55%

WITHDRAWN: Targeting mTORC1/2 with OSI-027 inhibits proliferation and migration of keloid keratinocytes

Liu

Wang

et al. 2018

Oncotarget

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Keloid is a dermal proliferative disorder characterized by the excessive keratinocyte proliferation and migration. mTOR over-activation is involved in the process. Here, we show that both mTOR complex 1 (mTORC1) and mTORC2 were hyper-activated in keloid-derived primary keratinocytes. OSI-027, an mTOR kinase inhibitor, potently inhibited proliferation and migration of keloid keratinocytes. OSI-027 disrupted the assembly of mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-RictormLST8). Further, OSI-027 completely blocked the phosphorylations of the mTORC1 substrates (S6K1, S6 and 4EBP1) and the mTORC2 substrate (AKT, at Ser-473). OSI-027 was potent than rapamycin in inhibiting keloid keratinocytes. Moreover, restoring mTORC1 activation by the introduction of the constitutively active S6K1 only partly alleviated OSI-027-induced suppression on keloid keratinocytes. Notably, mTOR2 inhibition by Rictor siRNA also inhibited keloid keratinocyte proliferation and migration, although less efficiently than OSI-027. Together, concurrent targeting of mTORC1/2 by OSI-027 potently inhibits keloid keratinocyte proliferation and migration.www.impactjournals.com/oncotarget/ Vol.9, (No.1), Supplement 1, pp: s147-s154

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“…Preliminary clinical data suggested a negative predictive role for tumors harboring KRAS mutations in response to mTORC1 inhibitors (37). Nevertheless, efficacy of mTORC1/2 inhibitors was observed in KRAS/BRAF-mutant colorectal cancer xenograft models, and PI3K/mTOR inhibitors induced tumor regressions in genetically engineered (wt) PIK3CA mouse models (38,39). Interestingly, the only patient with colorectal cancer achieving a partial response in our series had a molecular profile with a simultaneous PIK3CA and KRAS mutation.…”

Section: Discussionmentioning

confidence: 70%

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Dienstmann

Serpico

Rodón

et al. 2012

Molecular Cancer Therapeutics

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Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered phase I trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was conducted in 254 patients: KRAS mutations (80 of 254, 31.5%), BRAF mutations (24 of 196, 12.2%), PIK3CA mutations (15 of 114, 13.2%), KRAS and PIK3CA mutations (9 of 114, 7.9%), low PTEN expression (97 of 183, 53.0%), and high pMET expression (38 of 64, 59.4%). In total, 68 patients received 82 different MTAs: phosphoinositide 3-kinase (PI3K) pathway inhibitor (if PIK3CA mutation, n ¼ 10; or low PTEN, n ¼ 32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n ¼ 10; or BRAF mutation, n ¼ 1), second-generation anti-EGF receptor monoclonal antibodies (if wild-type KRAS, n ¼ 11), anti-hepatocyte growth factor monoclonal antibody (if high pMET, n ¼ 10), mTOR inhibitor plus anti-insulin-like growth factor-1 receptor monoclonal antibody (if low PTEN, n ¼ 5), and BRAF inhibitor (if BRAF mutation, n ¼ 3). Median time-to-treatment failure on MTA was 7.9 versus 16.3 weeks for their prior systemic antitumor therapy (P < 0.001). Partial response was seen in 1 patient [1.2%, PI3K inhibitor with PIK3CA mutation] and stable disease >16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory patients with colorectal cancer with targeted agents in phase I trials based on the current molecular profile does not confer a significant clinical benefit. Mol Cancer Ther; 11(9); 2062-71. Ó2012 AACR.

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Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin

Cited by 181 publications

References 31 publications

CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

WITHDRAWN: Targeting mTORC1/2 with OSI-027 inhibits proliferation and migration of keloid keratinocytes

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

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