Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma
Abstract
:1. Introduction
2. The mTOR Signaling Pathway
3. Regulation of the mTOR Pathway in Liver Diseases and HCC
4. Targeting mTOR Signaling in HCC: Experimental Models
4.1. Ursodeoxycholic Acid (UDCA)
4.2. Rapalogs
4.3. Second-Generation mTOR Inhibitors in HCC
4.4. Sorafenib
4.5. Combination of mTOR Inhibitors in HCC
5. Targeting mTOR Signaling in HCC: From the Bench to the Clinic
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
HCC | Hepatocellular carcinoma |
NASH | Non-alcoholic steatohepatitis |
mTOR | Mechanistic target of rapamycin |
PI3K mTORC DEPTOR Raptor RTKs ALD ULK1 TFEB SREBP1 HBV HCV UDCA TOR-KIs | Phosphoinositide 3-kinase mTOR complex DEP domain-containing mTOR-interacting protein Regulatory-associated protein of mTOR Receptor tyrosine kinases Alcoholic liver disease Unc-51-like kinase 1 Transcription factor EB Sterol regulatory element binding protein-1 Hepatitis B virus Hepatitis C virus Ursodeoxycholic acid mTOR kinase inhibitors |
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Drug Name | Pharmacological Group | Primary Target(s) | Licensed for | Pros and Cons |
---|---|---|---|---|
Sorafenib | Multikinase inhibitor | VEGFR, PDFGR, c-Kit, c-RAF and B-RAF | Standard of care for advanced unresectable HCC | Reduced tolerability, limited efficacy. Highly toxic when combined with mTOR inhibitors. |
Rapamycin (sirolimus) and everolimus | mTOR inhibitor | Intracellular receptor FKBP12. Inhibition of mTORC1 (and mTORC2 to a lesser extent) | Immunosuppression after liver transplantation in combination with calcineurin inhibitors | Inefficacious in monotherapy for advanced HCC. Potential effect as adjuvant therapy after liver transplantation to prevent tumor recurrence in selected patients. |
mTOR kinase inhibitors | mTOR inhibitor (ATP-competitive) | mTOR kinase domain. Inhibit both mTORC1 and mTORC2 | Under investigation for advanced HCC | Ongoing clinical trials in HCC. Safety and efficacy still to be determined. |
UDCA (and derivatives) | Bile acid | mTOR signalling pathway | Cholestatic diseases | Anti-tumor effect in preclinical models of HCC. Very well tolerated. No proven benefit for HCC in humans. |
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Ferrín, G.; Guerrero, M.; Amado, V.; Rodríguez-Perálvarez, M.; De la Mata, M. Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma. Int. J. Mol. Sci. 2020, 21, 1266. https://doi.org/10.3390/ijms21041266
Ferrín G, Guerrero M, Amado V, Rodríguez-Perálvarez M, De la Mata M. Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma. International Journal of Molecular Sciences. 2020; 21(4):1266. https://doi.org/10.3390/ijms21041266
Chicago/Turabian StyleFerrín, Gustavo, Marta Guerrero, Víctor Amado, Manuel Rodríguez-Perálvarez, and Manuel De la Mata. 2020. "Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma" International Journal of Molecular Sciences 21, no. 4: 1266. https://doi.org/10.3390/ijms21041266