Authors: Arafath K. Najumudeen, Sigrid K. Fey, Laura M. Millett, Catriona A. Ford, Kathryn Gilroy, Nuray Gunduz, Rachel A. Ridgway, Eve Anderson, Douglas Strathdee, William Clark, Colin Nixon, Jennifer P. Morton, Andrew D. Campbell, Owen J. Sansom
Published: 2024-01-02
DOI: 10.1038/s41467-023-44342-4
Source: Full article
AbstractOncogenicKRASmutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence ofKRASallelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele inKRASmutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-typeKrasin the context of oncogenicKras. Deletion of wild-typeKrasexacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-typeKraspotentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-typeKrasupon tumour initiation, progression and therapeutic response inKrasmutant CRC.