Synergistic anti-proliferative effect of mTOR inhibitor (rad001) plus gemcitabine on cholangiocarcinoma by decreasing choline kinase activity

Primary liver cancers, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), are highly lethal tumors, with high worldwide frequency and few effective treatment options. The mammalian target of rapamycin (mTOR) complex is a central regulator of cell growth and metabolism that integrates inputs from amino acids, nutrients, and extracellular signals. The mTOR protein is incorporated into two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Specifically, mTORC1 regulates protein synthesis, glucose and lipid metabolism, and autophagy, whereas mTORC2 promotes liver tumorigenesis through modulating the adenine/cytosine/guanine family of serine/threonine kinases, especially the protein kinase B proteins. In human HCC and iCCA samples, genomics analyses have revealed the frequent deregulation of the mTOR complexes. Both in vitro and in vivo studies have demonstrated the key role of mTORC1 and mTORC2 in liver‐tumor development and progression. The first‐generation mTOR inhibitors have been evaluated for effectiveness in liver‐tumor treatment and have provided unsatisfactory results. Current research efforts are devoted to generating more efficacious mTOR inhibitors and identifying biomarkers for patient selection as well as for combination therapies. Here, we provide a comprehensive review of the mechanisms leading to a deregulated mTOR signaling cascade in liver cancers, the mechanisms whereby the mTOR pathway contributes to HCC and iCCA molecular pathogenesis, the therapeutic strategies, and the challenges to effectively inhibit mTOR in liver‐cancer treatment. Conclusion: Deregulated mTOR signaling significantly contributes to HCC and iCCA molecular pathogenesis. mTOR inhibitors, presumably administered in association with other drugs, might be effective against subsets of human liver tumors.

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“…( 57 ) In addition, combining gemcitabine and everolimus resulted in a synergistic antigrowth effect in iCCA cells in vitro and in vivo. ( 58 )…”

Section: First‐generation Mtor Inhibitors: Rapalogsmentioning

confidence: 99%

Role of the Mammalian Target of Rapamycin Pathway in Liver Cancer: From Molecular Genetics to Targeted Therapies

et al. 2020

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“…In addition, rapamycin was found to initiate AKT activation in CCA and inhibition of AKT by salubrinal potentiates the in vitro and in vivo efficacy of rapamycin in CCA both [95]. In terms of combination of rapalogs and cytotoxic agents, our group reported gemcitabine plus everolimus combination showed synergistic effect in the CCA cells in vitro and in vivo [96].…”

Section: Preclinical Studies Of Mtor Inhibitors In Btcmentioning

confidence: 99%

mTOR Inhibitors in Advanced Biliary Tract Cancers

Chen

Yeh

2019

IJMS

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Patients with advanced biliary tract cancers (BTCs), including cholangiocarcinoma (CCA), have poor prognosis so novel treatment is warranted for advanced BTC. In current review, we discuss the limitations of current treatment in BTC, the importance of mTOR signalling in BTC, and the possible role of mTOR inhibitors as a future treatment in BTC. Chemotherapy with gemcitabine-based chemotherapy is still the standard of care and no targeted therapy has been established in advanced BTC. PI3K/AKT/mTOR signaling pathway linking to several other pathways and networks regulates cancer proliferation and progression. Emerging evidences reveal mTOR activation is associated with tumorigenesis and drug-resistance in BTC. Rapalogs, such as sirolimus and everolimus, partially inhibit mTOR complex 1 (mTORC1) and exhibit anti-cancer activity in vitro and in vivo in BTC. Rapalogs in clinical trials demonstrate some activity in patients with advanced BTC. New-generation mTOR inhibitors against ATP-binding pocket inhibit both TORC1 and TORC2 and demonstrate more potent anti-tumor effects in vitro and in vivo, however, prospective clinical trials are warranted to prove its efficacy in patients with advanced BTC.

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“…The combination of everolimus and gemcitabine synergistically enhanced their therapeutic effects in cell lines of various types of malignancies, including pancreatic cancer [ 38 ], cholangiocarcinoma [ 39 , 40 ], bladder cancer [ 41 ], and non-Hodgkin lymphoma [ 42 ]. The anti-tumor effects of this combination were mainly mediated by the induction of apoptosis and suppression of proliferative activity.…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

Yamamoto

Togashi

Sugai

et al. 2022

Cancers

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Despite several clinical trials with encouraging findings, effective standard systemic therapies have yet to be established for malignant meningioma and the prognosis of these patients remains poor. Accumulating preclinical and clinical evidence suggests that gemcitabine is effective against malignant meningioma. To identify drugs with therapeutic effects that may be enhanced in combination with gemcitabine, we screened drugs that have been tested in preclinical and clinical trials for meningioma. In IOMM-Lee and HKBMM malignant meningioma cells, gemcitabine enhanced the growth inhibitory effects of the mTOR inhibitor everolimus, the clinical benefits of which have been demonstrated in patients with meningioma. The synergistic growth inhibitory effects of this combination were accompanied by cellular senescence characterized by an increase in senescence-associated β-galactosidase activity. To enhance the effects of this combination, we screened senolytic drugs that selectively kill senescent cells, and found that navitoclax, an inhibitor of anti-apoptotic BCL-2 family proteins, effectively reduced the number of viable malignant meningioma cells in combination with everolimus and gemcitabine by inducing apoptotic cell death. The suppression of tumor growth in vivo by the combination of everolimus with gemcitabine was significantly stronger than that by either treatment alone. Moreover, navitoclax, in combination with everolimus and gemcitabine, significantly reduced tumor sizes with an increase in the number of cleaved caspase-3-positive apoptotic cells. The present results suggest that the addition of gemcitabine with or without navitoclax to everolimus is a promising strategy that warrants further evaluation in future clinical trials for malignant meningioma.

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Synergistic anti-proliferative effect of mTOR inhibitor (rad001) plus gemcitabine on cholangiocarcinoma by decreasing choline kinase activity

Cited by 10 publications

References 38 publications

Role of the Mammalian Target of Rapamycin Pathway in Liver Cancer: From Molecular Genetics to Targeted Therapies

Role of the Mammalian Target of Rapamycin Pathway in Liver Cancer: From Molecular Genetics to Targeted Therapies

mTOR Inhibitors in Advanced Biliary Tract Cancers

Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

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