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- Title
RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways.
- Authors
Gudiño, Victoria; Pohl, Sebastian Öther-Gee; Billard, Caroline V.; Cammareri, Patrizia; Bolado, Alfonso; Aitken, Stuart; Stevenson, David; Hall, Adam E.; Agostino, Mark; Cassidy, John; Nixon, Colin; von Kriegsheim, Alex; Freile, Paz; Popplewell, Linda; Dickson, George; Murphy, Laura; Wheeler, Ann; Dunlop, Malcolm; Din, Farhat; Strathdee, Douglas
- 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. RAC1 is a downstream target of the Wnt signaling that promotes intestinal stem cell expansion and tumorigenesis. Here, the authors identify the specific splice variant RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment.
- Subjects
WNT signal transduction; COLORECTAL cancer; INTESTINES; EPIDERMAL growth factor receptors; PROGNOSIS
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-22531-3