Cancer modeling in colorectal organoids reveals intrinsic differences between oncogenic RAS and BRAF variants
Jasmin B. Post, Nizar Hami, Jeroen Lohuis, Marieke van de Ven, Renske de Korte-Grimmerink, Christina Stangl, Ellen Stelloo, Ingrid Verlaan, Jacco van Rheenen, Hugo J.G. Snippert
Received Date: 18th November 19
Colorectal cancers (CRCs) with oncogenic mutations in RAS and BRAF are associated with anti-EGFR therapy resistance. Consequently, all RAS mutant CRC patients are being excluded from this therapy. However, heterogeneity in drug response has been reported between RAS mutant CRC patients. It is poorly understood to what extent such differences are derived from different genetic backgrounds or intrinsic differences between the various RAS pathway mutations. Therefore, using CRISPR technology we generated an isogenic panel of patient-derived CRC organoids with various RAS pathway mutations (i.e. KRASG12D, BRAFV600E, KRASG13D and NRASG12D). All RAS pathway mutants promote ERK activation and tumor growth. However, KRASG12D and BRAFV600E mutations in particular conferred robust resistance to anti-EGFR therapy, both in vitro and in vivo. Moreover, untreated KRASG13D mutants showed fastest growth in mice but remained sensitive to anti-EGFR therapy. Together, introducing mutation-specific oncogene signaling in CRC organoids resembles clinical phenotypes and improves understanding of genotype-phenotype correlations.
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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.