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

Research output: Contribution to journal/periodicalArticleScientificpeer-review

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)112324
JournalCell Reports
Volume42
Issue number4
DOIs
Publication statusPublished - 25 Apr 2023

Keywords

  • Humans
  • Proto-Oncogene Proteins p21(ras)/metabolism
  • Colorectal Neoplasms/drug therapy
  • Vinorelbine/pharmacology
  • Drug Repositioning
  • Cell Line, Tumor
  • Colonic Neoplasms/drug therapy
  • Antineoplastic Agents/pharmacology
  • Organoids/metabolism

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