RT Journal Article
SR Electronic
T1 Cancer modeling in colorectal organoids reveals intrinsic differences between oncogenic <em>RAS</em> and <em>BRAF</em> variants
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 860122
DO 10.1101/860122
A1 Jasmin B. Post
A1 Nizar Hami
A1 Jeroen Lohuis
A1 Marieke van de Ven
A1 Renske de Korte-Grimmerink
A1 Christina Stangl
A1 Ellen Stelloo
A1 Ingrid Verlaan
A1 Jacco van Rheenen
A1 Hugo J.G. Snippert
YR 2019
UL http://biorxiv.org/content/early/2019/11/29/860122.abstract
AB 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.