| Autor: |
Sander Mertens, Maarten A. Huismans, Carla S. Verissimo, Bas Ponsioen, Rene Overmeer, Natalie Proost, Olaf van Tellingen, Marieke van de Ven, Harry Begthel, Sylvia F. Boj, Hans Clevers, Jeanine M.L. Roodhart, Johannes L. Bos, Hugo J.G. Snippert |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Cell Reports, Vol 42, Iss 4, Pp 112324- (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2023.112324 |
| Popis: |
Summary: Patient-derived organoids (PDOs) are widely heralded as a drug-screening platform to develop new anti-cancer therapies. Here, we use a drug-repurposing library to screen PDOs of colorectal cancer (CRC) to identify hidden vulnerabilities within therapy-induced phenotypes. Using a microscopy-based screen that accurately scores drug-induced cell killing, we have tested 414 putative anti-cancer drugs for their ability to switch the EGFRi/MEKi-induced cytostatic phenotype toward cytotoxicity. A majority of validated hits (9/37) are microtubule-targeting agents that are commonly used in clinical oncology, such as taxanes and vinca-alkaloids. One of these drugs, vinorelbine, is consistently effective across a panel of >25 different CRC PDOs, independent of RAS mutational status. Unlike vinorelbine alone, its combination with EGFR/MEK inhibition induces apoptosis at all stages of the cell cycle and shows tolerability and effective anti-tumor activity in vivo, setting the basis for a clinical trial to treat patients with metastatic RAS-mutant CRC. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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