Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer

Anna Lena Scherr, Andreas Mock, Georg Gdynia, Nathalie Schmitt, Christoph E. Heilig, Felix Korell, Praveen Rhadakrishnan, Paula Hoffmeister, Klaus H. Metzeler, Klaus Schulze-Osthoff, Anna L. Illert, Melanie Boerries, Jörg Trojan, Oliver Waidmann, Johanna Falkenhorst, Jens Siveke, Philipp J. Jost, Michael Bitzer, Nisar P. Malek, Loredana VecchioneIvan Jelas, Benedikt Brors, Hanno Glimm, Albrecht Stenzinger, Svetlana P. Grekova, Tobias Gehrig, Henning Schulze-Bergkamen, Dirk Jäger, Peter Schirmacher, Mathias Heikenwalder, Benjamin Goeppert, Martin Schneider, Stefan Fröhling, Bruno C. Köhler

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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.

Original languageEnglish
Article number875
JournalCell Death and Disease
Volume11
Issue number10
DOIs
StatePublished - 1 Oct 2020
Externally publishedYes

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