Schmitt, N. (Nathalie)

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    Bcl-x(L) as prognostic marker and potential therapeutic target in cholangiocarcinoma
    (2022) Banales, J.M. (Jesús M.); Stenzinger, A. (Albrecht); Köhler, B.C. (Bruno C.); Westphalen, C.B. (Christoph B.); Albrecht, T. (Thomas); Xu, K. (Kaiyu); Illert, A.L. (Anna L.); Kelmendi, E. (Eblina); Kessler, A. (Annika); Spiekermann, K. (Karsten); Ochsenreiter, S. (Sebastian); Hübschmann, D. (Daniel); Fröhling, S. (Stefan); Springfeld, C. (Christoph); Roessler, S. (Stephanie); Hoffmeister-Wittmann, P. (Paula); Nader, L. (Luisa); Siveke, J. (Jens); Jäger, D. (Dirk); Fritzsche, S. (Sarah); Goeppert, B. (Benjamin); Brors, B. (Benedikt); Boeck, S. (Stefan); Boerries, M. (Melanie); Uhrig, S. (Sebastian); Schmitt, N. (Nathalie); Günther, M. (Michael); Bauer, S. (Sebastian); Korell, F. (Felix); Schulze-Osthoff, K. (Klaus); Kreutzfeld, S. (Simon); Horak, P. (Peter); Scherr, A.L. (Anna Lena); Sobol, B. (Benjamin); Trojan, J. (Jörg); Weichert, W. (Wilko); Hüllein, J. (Jennifer); Weiler, S. (Sofia); Glimm, H. (Hanno); Nichetti, F. (Federico); Bitzer, M. (Michael); Schirmacher, P. (Peter); Mock, A. (Andreas); Kindler, T. (Thomas); Heilig, C.E. (Christoph E.); Ormanns, S. (Steffen); Folprecht, G. (Gunnar); Klauschen, F. (Frederick)
    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.