Abstract Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, there is still much debate over the function of wild-type KRAS in tumour initiation, progression and therapeutic response. We have developed a genetically engineered mouse model which allows deletion of the wild-type copy of Kras in the context of an intact oncogenic Kras in colorectal cancer. We observe that in the presence of oncogenic Kras , wild-type Kras acts to restrain tumour growth. Mechanistically, deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while presence of wild-type Kras is associated with resistance to inhibition of MEK1/2 in KRASG12D driven tumours. Importantly, loss of wild-type Kras in oncogenic KRAS-driven aggressive tumours significantly alters tumour progression, metastasis while impacting tumour immune cell infiltration. This study demonstrates a suppressive role for wild-type Kras during colon tumour initiation and highlights the critical impact of wild-type Kras upon therapeutic response to MAPK and tumour progression in Kras mutant cancers. Highlights Wild-type KRAS suppresses mutant KRASG12D mediated proliferation and signalling in colorectal cancer models in vivo Concomitant 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 tumours Loss of wild-type KRAS inhibits metastasis of late-stage mutant KRAS colorectal cancer models.

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