Drug-repurposing screen on patient-derived organoids identifies therapy-induced vulnerability in KRAS-mutant colon cancer
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
Affiliations
Sander Mertens
Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
Maarten A. Huismans
Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
Carla S. Verissimo
Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
Bas Ponsioen
Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
Rene Overmeer
Hubrecht Organoid Technology (HUB), Utrecht, the Netherlands
Natalie Proost
Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
Olaf van Tellingen
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
Marieke van de Ven
Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
Harry Begthel
Oncode Institute, Hubrecht Institute-KNAW, University Medical Center Utrecht, Utrecht, the Netherlands
Sylvia F. Boj
Hubrecht Organoid Technology (HUB), Utrecht, the Netherlands
Hans Clevers
Oncode Institute, Hubrecht Institute-KNAW, University Medical Center Utrecht, Utrecht, the Netherlands
Jeanine M.L. Roodhart
Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
Johannes L. Bos
Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
Hugo J.G. Snippert
Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Corresponding author
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.
