Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening
- University Medical Center Utrecht, Netherlands
- Cancer Genomics Netherlands, Netherlands
- Netherlands Cancer Institute, Netherlands
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
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.
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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Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening
eLife 5:e18489.
https://doi.org/10.7554/eLife.18489
