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

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.

SUBMITTER: Scherr AL

PROVIDER: S-EPMC7568722 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Scherr Anna-Lena AL Mock Andreas A Gdynia Georg G Schmitt Nathalie N Heilig Christoph E CE Korell Felix F Rhadakrishnan Praveen P Hoffmeister Paula P Metzeler Klaus H KH Schulze-Osthoff Klaus K Illert Anna L AL Boerries Melanie M Trojan Jörg J Waidmann Oliver O Falkenhorst Johanna J Siveke Jens J Jost Philipp J PJ Bitzer Michael M Malek Nisar P NP Vecchione Loredana L Jelas Ivan I Brors Benedikt B Glimm Hanno H Stenzinger Albrecht A Grekova Svetlana P SP Gehrig Tobias T Schulze-Bergkamen Henning H Jäger Dirk D Schirmacher Peter P Heikenwalder Mathias M Goeppert Benjamin B Schneider Martin M Fröhling Stefan S Köhler Bruno C BC

Cell death & disease 20201017 10

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 antia ...[more]

PMID: 33070156

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Dataset Information

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

Publications

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

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