RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways. / 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; Sansom, Owen J; Myant, Kevin B.

In: Nature Communications, Vol. 12, No. 1, 2335, 20.04.2021.

Research output: Contribution to journalArticlepeer-review

Published
  • 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 von Kriegsheim
  • Paz Freile
  • Laura Murphy
  • Ann Wheeler
  • Malcolm Dunlop
  • Farhat Din
  • Douglas Strathdee
  • Owen J Sansom
  • Kevin B Myant

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.

Original languageEnglish
Article number2335
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 20 Apr 2021
This open access research output is licenced under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

ID: 41974859