1. Cancer Biology
  2. Developmental Biology
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Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening

  1. Carla S Verissimo
  2. René M Overmeer
  3. Bas Ponsioen
  4. Jarno Drost
  5. Sander Mertens
  6. Ingrid Verlaan-Klink
  7. Bastiaan van Gerwen
  8. Marieke van der Ven
  9. Marc Van de Wetering
  10. David A Egan
  11. René Bernards
  12. Hans Clevers
  13. Johannes L Bos
  14. Hugo J Snippert  Is a corresponding author
  1. University Medical Center Utrecht, Netherlands
  2. Cancer Genomics Netherlands, Netherlands
  3. Netherlands Cancer Institute, Netherlands
Research Article
  • Cited 51
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Cite this article as: eLife 2016;5:e18489 doi: 10.7554/eLife.18489

Abstract

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.

Article and author information

Author details

  1. Carla S Verissimo

    Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  2. René M Overmeer

    Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  3. Bas Ponsioen

    Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  4. Jarno Drost

    Cancer Genomics Netherlands, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  5. Sander Mertens

    Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  6. Ingrid Verlaan-Klink

    Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  7. Bastiaan van Gerwen

    Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  8. Marieke van der Ven

    Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  9. Marc Van de Wetering

    Cancer Genomics Netherlands, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  10. David A Egan

    Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  11. René Bernards

    Cancer Genomics Netherlands, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  12. Hans Clevers

    Cancer Genomics Netherlands, Utrecht, Netherlands
    Competing interests
    Hans Clevers, An inventor on several patents involving the organoid culture system (USPTO 20120196312 and 20140256037).
  13. Johannes L Bos

    Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  14. Hugo J Snippert

    Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
    For correspondence
    h.j.g.snippert@umcutrecht.nl
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4189-5213

Funding

Stand Up To Cancer

  • Hans Clevers
  • Johannes L Bos

KWF Kankerbestrijding

  • Hugo J Snippert

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

  • Jarno Drost

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Approval for this study was obtained by the local animal experimental committee at The Netherlands Cancer Institute (DEC-NKI). (DEC-NKI; OZP=12012 and WP5727 and WP5689).All of the animals were handled according to approved institutional animal care and use committee.

Reviewing Editor

  1. Jonathan A Cooper, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: June 5, 2016
  2. Accepted: November 14, 2016
  3. Accepted Manuscript published: November 15, 2016 (version 1)
  4. Version of Record published: November 29, 2016 (version 2)

Copyright

© 2016, Verissimo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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