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

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 uptake. Inhibiting WNT activity pharmacologically suppressed trametinib resistance in RAP tumours and more genetically complex ‘patient avatar’ models. The efficacy of WNT/MEK drug inhibitor combinations was further enhanced by targeting brm, shg, ago, rhoGAPp190, and upf1, potential biomarkers for patients responsive to this dual therapeutic approach. These findings shed light on how genetic complexity impacts drug resistance and a strategy to overcome it.