Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
Inflammatory Bowel Disease Unit, Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) - CIBEREHD, Barcelona, Spain.
Nat Commun. 2021 Apr 20;12(1):2335. doi: 10.1038/s41467-021-22531-3.
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.
目前治疗结直肠癌的方法疗效有限，且在治疗过程中经常会出现获得性耐药，即使对患者进行了分层。了解促进治疗耐药的机制可能会导致开发新的治疗方法，补充现有治疗方法，并改善患者的预后。在这里，我们确定 RAC1B 是结直肠肿瘤发生的重要介质，也是增强 EGFR 抑制剂治疗效果的潜在靶点。我们发现，人结直肠癌中高 RAC1B 表达与侵袭性疾病和不良预后相关，在小鼠结直肠肿瘤模型中删除 Rac1b 可降低肿瘤发生。我们证明 RAC1B 与 EGFR 信号通路相互作用，并需要其才能有效地激活该通路。此外，RAC1B 抑制使西妥昔单抗耐药的人类肿瘤类器官对 EGFR 抑制的作用敏感，这为提高结直肠癌中 EGFR 抑制剂的临床疗效提供了一个潜在的治疗靶点。
