Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-11-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/18489 |
| _version_ | 1811235899203125248 |
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| author | Carla S Verissimo René M Overmeer Bas Ponsioen Jarno Drost Sander Mertens Ingrid Verlaan-Klink Bastiaan van Gerwen Marieke van der Ven Marc van de Wetering David A Egan René Bernards Hans Clevers Johannes L Bos Hugo J Snippert |
| author_facet | Carla S Verissimo René M Overmeer Bas Ponsioen Jarno Drost Sander Mertens Ingrid Verlaan-Klink Bastiaan van Gerwen Marieke van der Ven Marc van de Wetering David A Egan René Bernards Hans Clevers Johannes L Bos Hugo J Snippert |
| author_sort | Carla S Verissimo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:00:25Z |
| format | Article |
| id | doaj.art-7501d8e3fc1b4a42aa7676d2bb0a2f09 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:00:25Z |
| publishDate | 2016-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7501d8e3fc1b4a42aa7676d2bb0a2f092022-12-22T03:33:53ZengeLife Sciences Publications LtdeLife2050-084X2016-11-01510.7554/eLife.18489Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screeningCarla S Verissimo0René M Overmeer1Bas Ponsioen2Jarno Drost3Sander Mertens4Ingrid Verlaan-Klink5Bastiaan van Gerwen6Marieke van der Ven7Marc van de Wetering8David A Egan9René Bernards10Hans Clevers11Johannes L Bos12Hugo J Snippert13Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands; Cancer Genomics Netherlands, Utrecht, NetherlandsMolecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands; Cancer Genomics Netherlands, Utrecht, NetherlandsMolecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands; Cancer Genomics Netherlands, Utrecht, NetherlandsCancer Genomics Netherlands, Utrecht, Netherlands; Hubrecht Institute – KNAW, University Medical Center Utrecht, Utrecht, The NetherlandsMolecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands; Cancer Genomics Netherlands, Utrecht, NetherlandsMolecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands; Cancer Genomics Netherlands, Utrecht, NetherlandsMouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, The NetherlandsMouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, The NetherlandsCancer Genomics Netherlands, Utrecht, Netherlands; Hubrecht Institute – KNAW, University Medical Center Utrecht, Utrecht, The NetherlandsCell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The NetherlandsCancer Genomics Netherlands, Utrecht, Netherlands; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The NetherlandsCancer Genomics Netherlands, Utrecht, Netherlands; Hubrecht Institute – KNAW, University Medical Center Utrecht, Utrecht, The NetherlandsMolecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands; Cancer Genomics Netherlands, Utrecht, NetherlandsMolecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands; Cancer Genomics Netherlands, Utrecht, NetherlandsColorectal 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.https://elifesciences.org/articles/18489organoidscolorectal cancertargeted therapyKRAS |
| spellingShingle | Carla S Verissimo René M Overmeer Bas Ponsioen Jarno Drost Sander Mertens Ingrid Verlaan-Klink Bastiaan van Gerwen Marieke van der Ven Marc van de Wetering David A Egan René Bernards Hans Clevers Johannes L Bos Hugo J Snippert Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening eLife organoids colorectal cancer targeted therapy KRAS |
| title | Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening |
| title_full | Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening |
| title_fullStr | Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening |
| title_full_unstemmed | Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening |
| title_short | Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening |
| title_sort | targeting mutant ras in patient derived colorectal cancer organoids by combinatorial drug screening |
| topic | organoids colorectal cancer targeted therapy KRAS |
| url | https://elifesciences.org/articles/18489 |
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