mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer

Driscoll, David R.; Karim, Saadia A.; Sano, Makoto; Gay, David M.; Jacob, Wright; Yu, Jun; Mizukami, Yusuke; Gopinathan, Aarthi; Jodrell, Duncan I.; Evans, T.R. Jeffry; Bardeesy, Nabeel; Hall, Michael N.; Quattrochi, Brian; Klimstra, David S.; Barry, Simon T.; Sansom, Owen J.; Lewis, Brian C.; Morton, Jennifer P.

doi:10.1158/0008-5472.can-16-0810

Cited by 64 publications

(80 citation statements)

References 56 publications

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“…Previous studies have revealed that rapamycin therapy for PC patients was not effective and the efficacy of metformin in vivo was contradictory in many studies (30)(31)(32)(33)(34)(35)(36). The present study demonstrated the anti-tumor action of metformin and revealed the synergistic action of metformin and rapamycin in the treatment of PC cells by the downregulation of the mTOR signaling pathway.…”

Section: Discussionsupporting

confidence: 54%

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

2017

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Abstract. Previous studies have suggested that metformin may improve the survival rate of patients with pancreatic cancer (PC) by regulating the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin specifically targets mTOR. In the present study, the efficacy of metformin and rapamycin in isolation and combination were investigated for the treatment of PC. The efficacy of metformin and rapamycin in reducing the proliferation of PC cell line SW1990 in vitro and in vivo was evaluated. It was revealed that metformin (10 mmol/l) + rapamycin (2 ng/ml), metformin (15 mmol/l) + rapamycin (20 ng/ml) and metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly inhibited the viability of PC cells compared with untreated cells. Additionally, metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly suppressed the expression of phosphorylated mTOR compared with metformin or rapamycin alone. Using a xenograft tumor model, it was revealed that combination treatment significantly inhibited the growth of PC cells compared with monotherapy. The present study revealed that a combination of metformin and rapamycin synergistically inhibited the growth of PC in vitro and in vivo and may be a potential treatment option for patients with PC.

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Section: Discussionsupporting

confidence: 54%

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

2017

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“…48 However, studies in mice brought to evidence the important role of mTORC2 signaling in pancreatic tumorigenesis and suggest that dual mTORC1/2 inhibition might be promising. 49 Our data from human PC tumors showed an association between tumor budding and other adverse histologic features as adjacent organ and vein invasions. Interestingly, our data also provided a trend between the presence of tumor budding and high expression of ZEB-1.…”

Section: Discussionmentioning

confidence: 64%

“…The combination therapy of capecitabine (a prodrug of 5‐fluorouracil) and everolimus only showed a modest improvement in a phase II clinical trial as first‐line or second‐line treatment of PC . However, studies in mice brought to evidence the important role of mTORC2 signaling in pancreatic tumorigenesis and suggest that dual mTORC1/2 inhibition might be promising …”

Section: Discussionmentioning

confidence: 99%

Gemcitabine‐induced epithelial‐mesenchymal transition‐like changes sustain chemoresistance of pancreatic cancer cells of mesenchymal‐like phenotype

Amrani

Corfiotti

Corvaisier

et al. 2019

Molecular Carcinogenesis

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Growing body of evidence suggests that epithelial‐mesenchymal transition (EMT) is a critical process in tumor progression and chemoresistance in pancreatic cancer (PC). The aim of this study was to analyze the role of EMT‐like changes in acquisition of resistance to gemcitabine in pancreatic cells of the mesenchymal or epithelial phenotype. Therefore, chemoresistant BxPC‐3, Capan‐2, Panc‐1, and MiaPaca‐2 cells were selected by chronic exposure to increasing concentrations of gemcitabine. We show that gemcitabine‐resistant Panc‐1 and MiaPaca‐2 cells of mesenchymal‐like phenotype undergo further EMT‐like molecular changes mediated by ERK‐ZEB‐1 pathway, and that inhibition of ERK1/2 phosphorylation or ZEB‐1 expression resulted in a decrease in chemoresistance. Conversely, gemcitabine‐resistant BxPC‐3 and Capan‐2 cells of epithelial‐like phenotype did not show such typical EMT‐like molecular changes although the expression of the tight junction marker occludin could be found decreased. In pancreatic cancer patients, high ZEB‐1 expression was associated with tumor invasion and tumor budding. In addition, tumor budding was essentially observed in patients treated with neoadjuvant chemotherapy. These findings support the notion that gemcitabine treatment induces EMT‐like changes that sustain invasion and chemoresistance in PC cells.

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“…This may further be explained by mTORC1 being involved in complex negative feedback loops that restrain upstream signalling. More recently developed dual ATP-competitive agents that target mTORC1/mTORC2 have shown favourable results [207,208] with AZD2014 effectively inhibiting PDAC cell division (G1 arrest), proliferation, and invasion in vitro [158,160] and prolonging survival in the KPC mouse model of PDAC [109,208,209]. More recently developed dual ATP-competitive agents that target mTORC1/mTORC2 have shown favourable results [207,208] with AZD2014 effectively inhibiting PDAC cell division (G1 arrest), proliferation, and invasion in vitro [158,160] and prolonging survival in the KPC mouse model of PDAC [109,208,209].…”

Section: Modulation Of the Upstream And Downstream Src Signalling Commentioning

confidence: 99%

“…For example, inhibition of mTORC1 drives activation of PI3K-, AKT-or ERK pathways [205], which in turn limits the efficacy of mTORC-inhibitors as targeted therapies [206]. More recently developed dual ATP-competitive agents that target mTORC1/mTORC2 have shown favourable results [207,208] with AZD2014 effectively inhibiting PDAC cell division (G1 arrest), proliferation, and invasion in vitro [158,160] and prolonging survival in the KPC mouse model of PDAC [109,208,209]. However there is still some debate as to whether blocking mTORC1/2 leads to the adaptive activation of the PI3K-AKT pathway [209], and consequently whether multiple targeting of this network is required to effectively interfere with both branches of adaptive signalling and to elicit a durable therapeutic response.…”

Section: Modulation Of the Upstream And Downstream Src Signalling Commentioning

confidence: 99%

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

et al. 2019

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Pancreatic cancer, a disease with extremely poor prognosis, has been notoriously resistant to virtually all forms of treatment. The dynamic crosstalk that occurs between tumour cells and the surrounding stroma, frequently mediated by intricate Src/FAK signalling, is increasingly recognised as a key player in pancreatic tumourigenesis, disease progression and therapeutic resistance. These important cues are fundamental for defining the invasive potential of pancreatic tumours, and several components of the Src and downstream effector signalling have been proposed as potent anticancer therapeutic targets. Consequently, numerous agents that block this complex network are being extensively investigated as potential antiinvasive and antimetastatic therapeutic agents for this disease. In this review, we will discuss the latest evidence of Src signalling in PDAC progression, fibrotic response and resistance to therapy. We will examine future opportunities for the development and implementation of more effective combination regimens, targeting key components of the oncogenic Src signalling axis, and in the context of a precision medicine‐guided approach.

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mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer

Cited by 64 publications

References 56 publications

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

Gemcitabine‐induced epithelial‐mesenchymal transition‐like changes sustain chemoresistance of pancreatic cancer cells of mesenchymal‐like phenotype

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

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