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WNT signalling promotes NF-κB activation and drug resistance in KRAS-mutant colorectal cancer [pre-print]

Cong, B., Stamou, E., Pennel, K., Mckenzie, M., Matly, A., Gopinath, S., Edwards, J. and Cagan, R. (2023) WNT signalling promotes NF-κB activation and drug resistance in KRAS-mutant colorectal cancer [pre-print]. bioRxiv, (doi: 10.1101/2023.12.21.572810) (Unpublished)

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Abstract

Approximately 40% of colorectal cancer (CRC) cases are characterized by KRAS mutations, rendering them insensitive to most CRC 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 and human RAS mutant tumours. This upregulation required Toll-1 and Toll-9 and resulted in reduced efficacy of RAS pathway targeted drugs such as the MEK inhibitor trametinib. Inhibiting WNT activity pharmacologically significantly suppressed trametinib resistance in RAP tumours and more genetically complex RAP-containing 'patient avatar' models. WNT/MEK drug inhibitor combinations were further improved by targeting brm, shg, ago rhoGAPp190 and upf1, highlighting these genes as candidate biomarkers for patients sensitive to this duel approach. These findings shed light on how genetic complexity impacts drug resistance and proposes a therapeutic strategy to reverse this resistance.

Item Type:Articles
Status:Unpublished
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cong, Mr Bojie
Authors: Cong, B., Stamou, E., Pennel, K., Mckenzie, M., Matly, A., Gopinath, S., Edwards, J., and Cagan, R.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:bioRxiv
Publisher:bioRxiv
Copyright Holders:Copyright © The Authors/Funder
First Published:First published in BioRxiv
Publisher Policy:Reproduced under a Creative Commons licence
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