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

Victoria Gudiño, Sebastian Öther-Gee Pohl, Caroline V. Billard, Patrizia Cammareri, Alfonso Bolado, Stuart Aitken, David Stevenson, Adam E. Hall, Mark Agostino, John Cassidy, Colin Nixon, Alex Kriegsheim, Paz Freile, Linda Popplewell, George Dickson, Laura Murphy, Ann Wheeler, Malcolm Dunlop, Farhat Din, Douglas Strathdee, Owen J. Sansom and Kevin B. Myant ()
Additional contact information
Victoria Gudiño: The University of Edinburgh, Western General Hospital
Sebastian Öther-Gee Pohl: The University of Edinburgh, Western General Hospital
Caroline V. Billard: The University of Edinburgh, Western General Hospital
Patrizia Cammareri: The University of Edinburgh, Western General Hospital
Alfonso Bolado: The University of Edinburgh, Western General Hospital
Stuart Aitken: The University of Edinburgh, Western General Hospital
David Stevenson: Cancer Research UK Beatson Institute, Garscube Estate
Adam E. Hall: The University of Edinburgh, Western General Hospital
Mark Agostino: Curtin University
John Cassidy: University of Cambridge, Li Ka Shing Centre
Colin Nixon: Cancer Research UK Beatson Institute, Garscube Estate
Alex Kriegsheim: The University of Edinburgh, Western General Hospital
Paz Freile: The University of Edinburgh, Western General Hospital
Linda Popplewell: Royal Holloway - University of London
George Dickson: Royal Holloway - University of London
Laura Murphy: University of Edinburgh, Western General Hospital
Ann Wheeler: University of Edinburgh, Western General Hospital
Malcolm Dunlop: The University of Edinburgh, Western General Hospital
Farhat Din: The University of Edinburgh, Western General Hospital
Douglas Strathdee: Cancer Research UK Beatson Institute, Garscube Estate
Owen J. Sansom: Cancer Research UK Beatson Institute, Garscube Estate
Kevin B. Myant: The University of Edinburgh, Western General Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22531-3

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