WNT signalling promotes NF-κB activation and drug resistance in KRAS-mutant colorectal cancer.

ABSTRACT: Approximately 40% of colorectal cancer (CRC) cases are characterised by KRAS mutations, rendering them insensitive to most therapies. While the reasons for this resistance remain incompletely understood, one key aspect is genetic complexity: in CRC, oncogenic KRAS is most commonly paired with mutations that alter WNT and P53 activities ("RAP"). Here, we demonstrate that elevated WNT activity upregulates canonical NF-κB signalling in both Drosophila and human RAS mutant tumours. This upregulation was enhanced by P53 loss and required immune-associated factors Toll-1 and Toll-9. These changes reduced efficacy of Ras pathway-targeting drugs such as trametinib due to NF-κB-dependent enhancement of the glucuronidation detoxifying pathway, likely through modulating gene transcription and glucose

SUBMITTER: Cong B 

PROVIDER: S-EPMC12678608 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature