Wild-type KRAS Loss Alters Colorectal Cancer Development and Treatment Response
Martin A. Due?as
OniX - Connecting Ideas to Opportunities | Biotech Innovation Accelerator | Academic Research to Market | Strategic Partnerships | Funding Strategist
Summary: Research reveals the distinct roles of wild-type KRAS in colorectal cancer. Using mouse models, researchers demonstrated that deletion of wild-type KRAS alongside mutant KRAS G12D increases MAPK signaling and accelerates tumor initiation. However, this deletion also creates vulnerability to MEK1/2 inhibitors. In advanced colorectal cancer models, loss of wild-type KRAS reduces metastasis by modifying the tumor immune environment. The findings indicate that wild-type KRAS status significantly influences tumor initiation, progression, and treatment response in KRAS-mutant colorectal cancer.
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, 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-type Kras in the context of oncogenic Kras. 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 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-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.
References:
Najumudeen, A.K., Fey, S.K., Millett, L.M. et al. KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo. Nat Commun 15, 100 (2024). https://doi.org/10.1038/s41467-023-44342-4
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