Cancer modeling in colorectal organoids reveals intrinsic differences between oncogenic RAS and BRAF variants

Colorectal cancers (CRCs) with oncogenic mutations in and 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 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. , , and ). All RAS pathway mutants promote ERK activation and tumor growth. However, and mutations in particular conferred robust resistance to anti-EGFR therapy, both and . Moreover, untreated KRAS 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.