Abstract
Cholangiocarcinoma (CCA) is a rare but highly aggressive tumor entity for which systemic therapies only showed limited efficacy so far. As OSI-027—a dual kinase inhibitor targeting both mTOR complexes, mTORC1 and mTORC2 - showed improved anti-cancer effects, we sought to evaluate its impact on the migratory and metastatic capacity of CCA cells in vitro. We found that treatment with OSI-027 leads to reduced cell mobility and migration as well as a reduced surviving fraction in colony-forming ability. While neither cell viability nor proliferation rate was affected, OSI-027 decreased the expression of MMP2 and MMP9. Moreover, survival as well as anti-apoptotic signaling was impaired upon the use of OSI-027 as determined by AKT and MAPK blotting. Dual targeting of mTORC1/2 might therefore be a viable option for anti-neoplastic therapy in CCA.
Highlights
Cholangiocarcinoma (CCA) arising from epithelial cells of the biliary tract, can be subdivided into an intra- and extrahepatic subtype depending on the anatomic localization
To investigate the effect of OSI-027 on the migration capacity of Cholangiocellular carcinoma (CCA) cells, we performed a wound closure assay over 120 h for HuCCA1 and HuCCT1 cells exposed to 100–500 nM of the dual kinase inhibitor (Figure 1)
We assessed the role of Mammalian target of rapamycin complex 1 (mTORC1)/2 inhibition in tumor cell survival and migration in intrahepatic cholangiocellular carcinoma (iCCA)
Summary
Cholangiocarcinoma (CCA) arising from epithelial cells of the biliary tract, can be subdivided into an intra- and extrahepatic subtype (iCCA and eCCA) depending on the anatomic localization. No targeted therapy has entered the clinical routine for Abbreviations: 4E-BP1, Eukaryotic translation initiation factor 4E-binding protein 1; AKT, Protein kinase B; ATP, Adenosine triphosphate; BrdU, Bromdesoxyuridin; CCA, Cholangiocellular carcinoma; iCCA, Intrahepatic cholangiocellular carcinoma; CDK4/6, Cyclin dependent kinase 4/6; ECM, Extracellular matrix; EMT, Epithelial–mesenchymal transition; ERK, Extracellular-signal regulated kinases; MAPK, Mitogen-activated protein kinase; MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid; mTOR, Mammalian target of rapamycin; mTORC1, Mammalian target of rapamycin complex 1; mTORC2, Mammalian target of rapamycin complex 2; MMP2, Matrix metalloproteinase 2; MMP9, Matrix metalloproteinase 9; OSI-027, Trans-4-[4-Amino-5-(7-methoxy-1H-indol-2-yl)imidazo[5,1-f][1,2,4]triazin-7-yl]cyclohexanecarboxylic acid; PE, Plating efficiency; PI3K, Phosphoinositide 3-kinase; PP2A, Protein phosphatase 2; RAPTOR, Regulatory associated protein of mTOR; RICTOR, Rapamycin-insensitive companion of mTOR; RNAi, RNA interference; S6K, Ribosomal protein S6 kinase; Ser, Serine; SF, Surviving fraction; SGK1, Serum/glucocorticoid regulated kinase 1; Thr, Threonine; Tyr, Tyrosine.
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