RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways

Gudiño, V. et al. (2021) RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways. Nature Communications, 12, 2335. (doi: 10.1038/s41467-021-22531-3) (PMID:33879799) (PMCID:PMC8058071)

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Abstract

Current therapeutic options for treating colorectal cancer have little clinical efficacy and acquired resistance during treatment is common, even following patient stratification. Understanding the mechanisms that promote therapy resistance may lead to the development of novel therapeutic options that complement existing treatments and improve patient outcome. Here, we identify RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment. We find that high RAC1B expression in human colorectal cancer is associated with aggressive disease and poor prognosis and deletion of Rac1b in a mouse colorectal cancer model reduces tumourigenesis. We demonstrate that RAC1B interacts with, and is required for efficient activation of the EGFR signalling pathway. Moreover, RAC1B inhibition sensitises cetuximab resistant human tumour organoids to the effects of EGFR inhibition, outlining a potential therapeutic target for improving the clinical efficacy of EGFR inhibitors in colorectal cancer.

Item Type:Articles
Additional Information:K.B.M, V.G., C.B., P.C. and A.E.H. are supported by a CRUK Career Development Fellowship A19166 and an ERC Starting Grant 715782. O.J.S. is supported by CRUK grants A26825, A28233, A23390, A21139, A12481 and A17196 and an ERC Starting Grant 311301. F.V.N.D. was supported by Clinical Scientist Fellowships from CRUK (C26031/A11378) and Chief Scientist Office (SCAF/16/01). A.B. and A.v.K. carried out Mass Spectrometry analysis supported by the Wellcome Trust (Multiuser Equipment Grant, 208402/Z/17/Z).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nixon, Mr Colin and Myant, Dr Kevin and Cammareri, Dr Patrizia and Von Kriegsheim, Mr Alexander and Strathdee, Dr Douglas and Stevenson, Dr David and Sansom, Professor Owen
Authors: Gudiño, V., Pohl, S. Ö.-G., Billard, C. V., Cammareri, P., Bolado, A., Aitken, S., Stevenson, D., Hall, A. E., Agostino, M., Cassidy, J., Nixon, C., Von Kriegsheim, A., Freile, P., Popplewell, L., Dickson, G., Murphy, L., Wheeler, A., Dunlop, M., Din, F., Strathdee, D., Sansom, O. J., and Myant, K. B.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Research
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Nature Communications 12: 2335
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301989ACRClerate: Colorectal Cancer Stratified Medicine NetworkOwen SansomCancer Research UK (CRUK)C7932/A26825CS - Beatson Institute for Cancer Research