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Bcl-x(L) as prognostic marker and potential therapeutic target in cholangiocarcinoma

Autores: Hoffmeister-Wittmann, P.; Mock, A.; Nichetti, F.; Korell, F.; Heilig, C. E.; Scherr, A. L.; Gunther, M.; Albrecht, T.; Kelmendi, E.; Xu, K.; Nader, L.; Kessler, A.; Schmitt, N.; Fritzsche, S.; Weiler, S.; Sobol, B.; Stenzinger, A.; Boeck, S.; Westphalen, C. B.; Schulze-Osthoff, K.; Trojan, J.; Kindler, T.; Weichert, W.; Spiekermann, K.; Bitzer, M.; Folprecht, G.; Illert, A. L.; Boerries, M.; Klauschen, F.; Ochsenreiter, S.; Siveke, J.; Bauer, S.; Glimm, H.; Brors, B.; Huellein, J.; Huebschmann, D.; Uhrig, S.; Horak, P.; Kreutzfeld, S.; Bañales Asurmendi, Jesús; Springfeld, C.; Jaeger, D.; Schirmacher, P.; Roessler, S.; Ormanns, S.; Goeppert, B.; Froehling, S.; Kohler, B. C. (Autor de correspondencia)
Título de la revista: LIVER INTERNATIONAL
ISSN: 1478-3223
Volumen: 42
Número: 12
Páginas: 2855 - 2870
Fecha de publicación: 2022
Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x(L), Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-x(L) and Mcl-1. Expression of Bcl-x(L), Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-x(L) and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatemnt with specific small molecule inhibitors of Bcl-x(L) (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-x(L) induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-x(L) and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-x(L) in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-x(L) as a key protein in cell death resistance of CCA and may pave the way for clinical application.