Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Scherr, AL; Mock, A; Gdynia, G; Schmitt, N; Heilig, CE; Korell, F; Rhadakrishnan, P; Hoffmeister, P; Metzeler, KH; Schulze-Osthoff, K; Illert, AL; Boerries, M; Trojan, J; Waidmann, O; Falkenhorst, J; Siveke, J; Jost, PJ; Bitzer, M; Malek, NP; Vecchione, L; Jelas, I; Brors, B; Glimm, H; Stenzinger, A; Grekova, SP; Gehrig, T; Schulze-Bergkamen, H; Jäger, D; Schirmacher, P; Heikenwalder, M; Goeppert, B; Schneider, M; Fröhling, S; Köhler, BC.
Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer.
Cell Death Dis. 2020; 11(10):875
Doi: 10.1038/s41419-020-03092-7
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- Co-Autor*innen der Med Uni Graz
- Jost Philipp
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- 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.
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