Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening
Open accessAbstract
Colorectal cancer (CRC) organoids can be derived from almost all CRC patients and therefore capture the genetic diversity of this disease. We assembled a panel of CRC organoids carrying either wild-type or mutant RAS, as well as normal organoids and tumor organoids with a CRISPR-introduced oncogenic KRAS mutation. Using this panel, we evaluated RAS pathway inhibitors and drug combinations that are currently in clinical trial for RAS mutant cancers. Presence of mutant RAS correlated strongly with resistance to these targeted therapies. This was observed in tumorigenic as well as in normal organoids. Moreover, dual inhibition of the EGFR-MEK-ERK pathway in RAS mutant organoids induced a transient cell-cycle arrest rather than cell death. In vivo drug response of xenotransplanted RAS mutant organoids confirmed this growth arrest upon pan-HER/MEK combination therapy. Altogether, our studies demonstrate the potential of patient-derived CRC organoid libraries in evaluating inhibitors and drug combinations in a preclinical setting.
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Tumor organoids can be screened to select effective drugs from structurally similar candidates and to investigate synergic effects of drug combinations.
“Tumor organoids can be screened to select effective drugs from structurally similar candidates153 and investigate the synergic effects of different drugs for combination therapy154.”
From Organoids (2022) · cites this paper as [153]
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References 36 · Cited by 263
- Authors
- Verissimo, C. S., Overmeer, R. M., Ponsioen, B., Drost, J., Mertens, S., Verlaan-Klink, I., Gerwen, B. V., van der Ven, M., Wetering, M. V. D., Egan, D. A., Bernards, R., Clevers, H., Bos, J. L., & Snippert, H. J.
- Affiliations
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
- University Medical Center Utrecht (NL)
- The Netherlands Cancer Institute (NL)
- Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Corresponding author
- Snippert, Hugo J
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-11-15
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5127645
- OpenAlex
- W2551658846
- Cited by
- 263
- References
- 36
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 29 · 2023: 20 · 2022: 32 · 2021: 45 · 2020: 29 · 2019: 30 · 2018: 24 · 2017: 18
- FWCI
- 12.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Stand Up To Cancer
- KWF Kankerbestrijding
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- colorectal cancer, RAS mutations, patient-derived organoids, combinatorial drug screening, KRAS mutation, drug resistance, cell cycle arrest, xenotransplantation, preclinical drug testing
- MeSH terms
- Antineoplastic Agents, Drug Evaluation, Preclinical, Humans, Organoids, Recombination, Genetic, Colorectal Neoplasms, ras Proteins, Mutant Proteins, Clustered Regularly Interspaced Short Palindromic Repeats
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