Drug-repurposing screen on patient-derived organoids identifies therapy-induced vulnerability in KRAS-mutant colon cancer

  • Cell Rep. 2023 Mar 30;42(4):112324. doi: 10.1016/j.celrep.2023.112324.
Sander Mertens  1 ,  Maarten A Huismans  1 ,  Carla S Verissimo  1 ,  Bas Ponsioen  1 ,  Rene Overmeer  2 ,  Natalie Proost  3 ,  Olaf van Tellingen  4 ,  Marieke van de Ven  3 ,  Harry Begthel  5 ,  Sylvia F Boj  2 ,  Hans Clevers  5 ,  Jeanine M L Roodhart  6 ,  Johannes L Bos  1 ,  Hugo J G Snippert  7
Affiliations
  • 1. Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 2. Hubrecht Organoid Technology (HUB), Utrecht, the Netherlands.
  • 3. Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
  • 4. Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Division of Clinical Pharmacology, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
  • 5. Oncode Institute, Hubrecht Institute-KNAW, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 6. Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 7. Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: [email protected].
PMID: 37000626 DOI: 10.1016/j.celrep.2023.112324
Abstract

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.

Keywords
CP: Cancer; CP: Stem cell research; colorectal cancer; image-based drug screening; microtubule-targeting agents; organoids; targeted therapy.
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