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Scherr, Anna-Lena; Mock, Andreas; Gdynia, Georg; Schmitt, Nathalie; Heilig, Christoph E.; Korell, Felix; Rhadakrishnan, Praveen; Hoffmeister, Paula; Metzeler, Klaus H.; Schulze-Osthoff, Klaus; Illert, Anna L.; Boerries, Melanie; Trojan, Jörg; Waidmann, Oliver; Falkenhorst, Johanna; Siveke, Jens; Jost, Philipp J.; Bitzer, Michael; Malek, Nisar P.; Vecchione, Loredana; Jelas, Ivan; Brors, Benedikt; Glimm, Hanno; Stenzinger, Albrecht; Grekova, Svetlana P.; Gehrig, Tobias; Schulze-Bergkamen, Henning; Jaeger, Dirk; Schirmacher, Peter; Heikenwalder, Mathias; Goeppert, Benjamin; Schneider, Martin; Froehling, Stefan and Koehler, Bruno C. (2020): Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer. In: Cell Death & Disease, Vol. 11, No. 10, 875

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Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC. Consistently, pharmacologic and genetic inhibition of BCL-XL induced apoptosis in human CRC cell lines. In a combined treatment approach, targeting BCL-XL augmented the efficacy of chemotherapy in vitro, in a murine CRC model, and in human ex vivo derived CRC tissue cultures. Collectively, these data show that targeting of BCL-XL is efficient and safe in preclinical CRC models, observations that pave the way for clinical translation.

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