TY - JOUR TI - Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening AU - Verissimo, Carla S AU - Overmeer, René M AU - Ponsioen, Bas AU - Drost, Jarno AU - Mertens, Sander AU - Verlaan-Klink, Ingrid AU - Gerwen, Bastiaan van AU - van der Ven, Marieke AU - Wetering, Marc van de AU - Egan, David A AU - Bernards, René AU - Clevers, Hans AU - Bos, Johannes L AU - Snippert, Hugo J A2 - Cooper, Jonathan A VL - 5 PY - 2016 DA - 2016/11/15 SP - e18489 C1 - eLife 2016;5:e18489 DO - 10.7554/eLife.18489 UR - https://doi.org/10.7554/eLife.18489 AB - 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. KW - organoids KW - colorectal cancer KW - targeted therapy KW - KRAS JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -