Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer
| Autor: | Henning Schulze-Bergkamen, Jens T. Siveke, Benedikt Brors, Dirk Jäger, Melanie Boerries, Oliver Waidmann, Philipp J. Jost, Benjamin Goeppert, Paula Hoffmeister, Peter Schirmacher, Klaus Schulze-Osthoff, Johanna Falkenhorst, Christoph E. Heilig, Stefan Fröhling, Jörg Trojan, Hanno Glimm, Michael Bitzer, Nathalie Schmitt, Andreas Mock, Klaus H. Metzeler, Bruno Köhler, Loredana Vecchione, Georg Gdynia, Tobias Gehrig, Ivan Jelas, Nisar P. Malek, Svetlana P Grekova, Anna Lena Illert, Praveen Rhadakrishnan, Felix Korell, Albrecht Stenzinger, Martin Schneider, Anna-Lena Scherr, Mathias Heikenwalder |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Colorectal cancer medicine.medical_treatment Immunology Medizin bcl-X Protein Bcl-xL Apoptosis Antineoplastic Agents Article Cellular and Molecular Neuroscience Cell Line Tumor Medicine Humans lcsh:QH573-671 Cell Proliferation Chemotherapy biology business.industry lcsh:Cytology Translation (biology) Cell Biology medicine.disease In vitro Cancer therapeutic resistance Proto-Oncogene Proteins c-bcl-2 Cell culture Colonic Neoplasms Cancer research biology.protein Myeloid Cell Leukemia Sequence 1 Protein business Colorectal Neoplasms Ex vivo |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 11, Iss 10, Pp 1-16 (2020) |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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