The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 Upregulation in Osteosarcoma Preclinical Models

Pignochino, Ymera; Dell'Aglio, Carmine; Basiricò, Marco; Capozzi, Federica; Soster, Marco; Marchiò, Serena; Bruno, Stefania; Gammaitoni, Loretta; Sangiolo, Dario; Torchiaro, Erica; D’Ambrosio, Lorenzo; Fagioli, Franca; Ferrari, Stefano; Alberghini, Marco; Picci, Piero; Aglietta, Massimo; Grignani, Giovanni

doi:10.1158/1078-0432.ccr-12-2293

Cited by 100 publications

(117 citation statements)

References 36 publications

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“…Consistently, there were no significant differences in metastatic phenotypes between SMMC-7721-CYP3A5 and SMMC-7721-GFP cells following Rictor silencing. Several published studies have demonstrated that downregulation of the mTORC2 kinase activity usually resulted from the dissociation of the mTORC2 complex (15,(34)(35)(36). More importantly, the novel finding in our current study was that CYP3A5-mediated inactivation of p-AKT (S473) resulted from the inhibition of mTORC2 kinase activity, rather than disruption of the mTORC2 complex.…”

Section: Cyp3a5-induced Intracellular Ros Enrichment Is Responsible Fsupporting

confidence: 46%

“…Although multiple endogenous and exogenous substances have been reported to be involved in regulation of mTORC2 activity (15,(33)(34)(35)(36)(37)(38), second messengers, for instance ROS, regulating mTORC2 remains less well understood. Structural and biochemical characterization studies conducted on TOR (the yeast ortholog of mTOR) reveal that, owing to the presence of a redox-sensitive motif, the cellular stability or functionality of TOR is redox regulated (39).…”

Section: Cyp3a5-induced Intracellular Ros Enrichment Is Responsible Fmentioning

confidence: 99%

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CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling

et al. 2015

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CYP3A5 is a cytochrome P450 protein that functions in the liver metabolism of many carcinogens and cancer drugs. However, it has not been thought to directly affect cancer progression. In this study, we challenge this perspective by demonstrating that CYP3A5 is downregulated in many hepatocellular carcinomas (HCC), where it has an important role as a tumor suppressor that antagonizes the malignant phenotype. CYP3A5 was downregulated in multiple cohorts of human HCC examined. Lower CYP3A5 levels were associated with more aggressive vascular invasion, poor differentiation, shorter time to disease recurrence after treatment, and worse overall patient survival. Mechanistic investigations showed that CYP3A5 overexpression limited MMP2/9 function and suppressed HCC migration and invasion in vitro and in vivo by inhibiting AKT signaling. Notably, AKT phosphorylation at Ser473 was inhibited in CYP3A5-overexpressing HCC cells, an event requiring mTORC2 but not Rictor/mTOR complex formation. CYP3A5-induced ROS accumulation was found to be a critical upstream regulator of mTORC2 activity, consistent with evidence of reduced GSH redox activity in most clinical HCC specimens with reduced metastatic capacity. Taken together, our results defined CYP3A5 as a suppressor of HCC pathogenesis and metastasis with potential utility a prognostic biomarker. Cancer Res; 75(7); 1470-81. Ó2015 AACR.

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Section: Cyp3a5-induced Intracellular Ros Enrichment Is Responsible Fsupporting

confidence: 46%

Section: Cyp3a5-induced Intracellular Ros Enrichment Is Responsible Fmentioning

confidence: 99%

CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling

et al. 2015

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“…Preclinical models demonstrated encouraging data of dual sorafenib and everolimus administration against this escape mechanism. 61 Therefore, combination regimen of the mTOR inhibitor everolimus and sorafenib was evaluated in patients with unresectable OS. Although 45% of the patients presented six months of progression-free survival, the target of 50% was not reached.…”

Section: Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Deciphering signaling networks in osteosarcoma pathobiology

Adamopoulos

Gargalionis

Basdra

et al. 2016

Exp Biol Med (Maywood)

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Osteosarcoma is the most frequent type of primary bone tumors among children and adolescents. During the past years, little progress has been made regarding prognosis of osteosarcoma patients, especially for those with metastatic disease. Genomic instability and gene alterations are common, but current data do not reveal a consistent and repeatable pattern of osteosarcoma development, thus paralleling the tumor's high heterogeneity. Critical signal transduction pathways have been implicated in osteosarcoma pathobiology and are being evaluated as therapeutic targets, including receptor activator for nuclear factor-kB (RANK), Wnt, Notch, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, and mechanotransduction pathways. Herein, we recapitulate and discuss recent advances in the context of molecular mechanisms and signaling networks that contribute to osteosarcoma progression and metastasis, towards patient-tailored and novel-targeted treatments.

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“…Therefore, the development of more efficacious combination therapies involving SOR and other agents appears to be an attractive approach for providing improved clinical outcomes in the treatment of OS. In a recent study it was demonstrated that combination therapies of SOR and other chemotherapeutic agents may result in synergistic or additive inhibitory effects on the growth of OS cells (14).…”

Section: Introductionmentioning

confidence: 99%

Synergistic growth inhibition by sorafenib and cisplatin in human osteosarcoma cells

et al. 2015

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Abstract. Molecular-targeted therapy has shown promise as a treatment for advanced osteosarcoma (OS). Sorafenib (SOR), a multikinase inhibitor, is the approved systemic drug of choice for OS, but has demonstrated limited benefits due to its toxicity and other adverse effects. Therapy strategies for reducing toxicity include using lower doses of SOR in combination with other complementary agents. Cisplatin (CDDP) has been shown to be a promising anticancer drug against various types of cancer including OS. In the present study, SOR was combined with CDDP to determine whether this combinatorial treatment suppressed tumor growth thereby simultaneously reducing doses of the two drugs for the treatment of OS. Human Saos-2 OS cells were treated with SOR and CDDP, alone and in combination, and the effect of these treatments on cell proliferation, colony formation, cell cycle, apoptosis, migration, and invasion, and involvement in receptor signaling, as well as tumor growth ability in nude mice was determined. It was found that the combination of low concentrations of SOR and CDDP significantly suppressed the cell proliferation, colony formation, migration and invasion, and induced cell apoptosis and cell cycle arrest in the G0/G1 stage, and suppressed tumor growth in a nude mouse model compared to the actions of either agent alone. The results also showed that SOR in combination with CDDP significantly suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), which may contribute to the inhibition of tumor growth. These results suggested that SOR in combination with CDDP acts synergistically in the treatment of OS.

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The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 Upregulation in Osteosarcoma Preclinical Models

Abstract: Purpose: The multikinase inhibitor sorafenib displays antitumor activity in preclinical models of osteosarcoma. However, in sorafenib-treated patients with metastatic-relapsed osteosarcoma, disease stabilization and tumor shrinkage were short-lived and drug resistance occurred.

Cited by 100 publications

References 36 publications

CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling

CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling

Deciphering signaling networks in osteosarcoma pathobiology

Synergistic growth inhibition by sorafenib and cisplatin in human osteosarcoma cells

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