KRASallelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancerin vivo

Abstract

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, there is still much debate over the function of wild-typeKRASin tumour initiation, progression and therapeutic response. We have developed a genetically engineered mouse model which allows deletion of the wild-type copy ofKrasin the context of an intact oncogenicKrasin colorectal cancer. We observe that in the presence of oncogenicKras, wild-typeKrasacts to restrain tumour growth. Mechanistically, deletion of wild-typeKrasexacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-typeKraspotentiates the oncogenic effect of KRASG12D, while presence of wild-typeKrasis associated with resistance to inhibition of MEK1/2 in KRASG12D driven tumours. Importantly, loss of wild-typeKrasin oncogenic KRAS-driven aggressive tumours significantly alters tumour progression, metastasis while impacting tumour immune cell infiltration. This study demonstrates a suppressive role for wild-typeKrasduring colon tumour initiation and highlights the critical impact of wild-typeKrasupon therapeutic response to MAPK and tumour progression inKrasmutant cancers.HighlightsWild-type KRAS suppresses mutant KRASG12D mediated proliferation and signalling in colorectal cancer modelsin vivoConcomitant loss of wild-type KRAS and activation of WNT signalling promotes mutant KRAS-driven tumour initiation.Wild-type KRAS promotes resistance to MAPK inhibition in KRAS mutant tumoursLoss of wild-type KRAS inhibits metastasis of late-stage mutant KRAS colorectal cancer models.