title: Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening.
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 oncogenicKRASmutation. 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.
authors.affiliation: Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.|Cancer Genomics Netherlands, Utrecht, Netherlands.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Verissimo
authors.affiliation: Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.|Cancer Genomics Netherlands, Utrecht, Netherlands.
authors.forename: René M
authors.initials: RM
authors.lastname: Overmeer
authors.affiliation: Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.|Cancer Genomics Netherlands, Utrecht, Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Ponsioen
authors.affiliation: Cancer Genomics Netherlands, Utrecht, Netherlands.|Hubrecht Institute - KNAW, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jarno
authors.initials: J
authors.lastname: Drost
authors.affiliation: Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.|Cancer Genomics Netherlands, Utrecht, Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Mertens
authors.affiliation: Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.|Cancer Genomics Netherlands, Utrecht, Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Verlaan-Klink
authors.affiliation: Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Bastiaan van
authors.initials: BV
authors.lastname: Gerwen
authors.affiliation: Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: van der Ven
authors.affiliation: Cancer Genomics Netherlands, Utrecht, Netherlands.|Hubrecht Institute - KNAW, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marc van de
authors.initials: MV
authors.lastname: Wetering
authors.affiliation: Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: David A
authors.initials: DA
authors.lastname: Egan
authors.affiliation: Cancer Genomics Netherlands, Utrecht, Netherlands.|Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Bernards
authors.affiliation: Cancer Genomics Netherlands, Utrecht, Netherlands.|Hubrecht Institute - KNAW, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.|Cancer Genomics Netherlands, Utrecht, Netherlands.
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bos
authors.affiliation: Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.|Cancer Genomics Netherlands, Utrecht, Netherlands.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Snippert
mesh_terms: D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000494:pharmacology*; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D050505:Mutant Proteins / Q000037:antagonists & inhibitors*; D009940:Organoids / Q000187:drug effects*; D011995:Recombination, Genetic; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D050505:Mutant Proteins; D018631:ras Proteins
keywords: KRAS; cancer biology; colorectal cancer; developmental biology; human; organoids; stem cells; targeted therapy