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

• Published in: Cell death & disease 2020-10, Vol.11 (10), p.875-875, Article 875
• Main Authors: 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, Jäger, Dirk, Schirmacher, Peter, Heikenwalder, Mathias, Goeppert, Benjamin, Schneider, Martin, Fröhling, Stefan, Köhler, Bruno C.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/2; 13/51; 13/89; 38/91; 631/67/1059/2326; 631/80/82/23; 64/60; 692/699/67/1504/1885; 82/80; 96/31; Antibodies; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; bcl-X Protein - drug effects; bcl-X Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Proliferation - drug effects; Colonic Neoplasms - drug therapy; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Humans; Immunology; Life Sciences; Myeloid Cell Leukemia Sequence 1 Protein - drug effects; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Proto-Oncogene Proteins c-bcl-2 - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-03092-7

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.