Drug-repurposing screen on patient-derived organoids identifies therapy-induced vulnerability in KRAS-mutant colon cancer
Mertens, Sander; Huismans, Maarten A; Verissimo, Carla S; Ponsioen, Bas; Overmeer, Rene; Proost, Natalie; van Tellingen, Olaf; van de Ven, Marieke; Begthel, Harry; Boj, Sylvia F; Clevers, Hans; Roodhart, Jeanine M L; Bos, Johannes L; Snippert, Hugo J G
(2023) Cell Reports, volume 42, issue 4
(Article)
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
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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.
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Keywords: colorectal cancer, CP: Cancer, CP: Stem cell research, image-based drug screening, microtubule-targeting agents, organoids, targeted therapy, General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 2211-1247
Publisher: Cell Press
Note: Funding Information: We thank all lab members for reagents, suggestions, and discussions. We thank Prof. Dr. O. Kranenburg (Department of Surgical Oncology, UMC Utrecht Cancer Centre) for providing TOR PDOs. This work is funded by the Gravitation Program “CancerGenomics.nl” from the Netherlands Organization for Scientific Research (NWO), a grant from the Dutch Cancer Society (KWF/UU2013-6070 to H.J.G.S.), an ERC starting grant (IntratumoralNiche to H.J.G.S.), a KWF/Alpe d'HuZes grant (J.L.B. and H.C.), and a “Stand Up to Cancer” International Translational Cancer Research grant (J.L.B. and H.C.). Stand Up to Cancer is a program administered by the American Association for Cancer Research. The Mouse Clinic for Cancer and Aging (N.P. O.v.T. and M.v.d.V.) is supported by National Roadmap grant for Large-Scale Research Facilities of the Netherlands Organization for Scientific Research (NWO). The Oncode Institute is partly financed by the Dutch Cancer Society. H.C. J.L.B. and H.J.G.S. conceived the project. S.M. and H.J.G.S. designed experiments. S.M. M.A.H. C.S.V. B.P. R.O. and H.B. performed experiments. N.P. O.v.T. and M.v.d.V. performed mouse experiments. S.M. S.F.B. J.M.L.R. and H.J.G.S. analyzed data. S.M. and H.J.G.S. wrote the manuscript. S.M. C.S.V. J.L.B. and H.J.G.S. are inventors on a patent concerning the combination of MTAs with targeted inhibition of the EGFR-MAPK-signaling pathway. C.S.V. R.O. and S.F.B. are employed by Hubrecht Organoid Technology, which holds the exclusive license to the organoid technology. H.C. is an inventor of several patents related to organoid technology; his full disclosure is given at https://www.uu.nl/staff/JCClevers/. Funding Information: We thank all lab members for reagents, suggestions, and discussions. We thank Prof. Dr. O. Kranenburg (Department of Surgical Oncology, UMC Utrecht Cancer Centre) for providing TOR PDOs. This work is funded by the Gravitation Program “CancerGenomics.nl” from the Netherlands Organization for Scientific Research ( NWO ), a grant from the Dutch Cancer Society ( KWF/UU2013-6070 to H.J.G.S.), an ERC starting grant (IntratumoralNiche to H.J.G.S.), a KWF/Alpe d'HuZes grant (J.L.B. and H.C.), and a “Stand Up to Cancer” International Translational Cancer Research grant (J.L.B. and H.C.). Stand Up to Cancer is a program administered by the American Association for Cancer Research. The Mouse Clinic for Cancer and Aging (N.P., O.v.T., and M.v.d.V.) is supported by National Roadmap grant for Large-Scale Research Facilities of the Netherlands Organization for Scientific Research (NWO). The Oncode Institute is partly financed by the Dutch Cancer Society. Publisher Copyright: © 2023 The Authors
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