德克萨斯大学Subrata Sen小组宣布他们发现了RASH3D19在KRAS突变型癌症中通过正反馈回路介导RAS激活。相关论文于2025年12月1日发表在《自然—细胞生物学》杂志上。

在这里，课题组报道RASH3D19通过涉及KRAS-microRNA信号轴的正反馈回路作为RAS通路激活的中介。KRAS诱导的miR-222抑制ETS1的表达和miR-301a的下游转激活，导致其靶点RASH3D19的升高。RASH3D19通过促进EGFR与SOS2、GRB2、SHP2和GAB1复合物的二聚化和相互作用，促进RAS通路的激活。表达KRAS的突变型癌细胞中RASH3D19基因缺失在体外和体内表现出生长迟缓，并使胰腺导管腺癌和结直肠癌细胞、类器官和异种移植物对突变型KRAS抑制剂敏感，抑制RAS通路的反馈再激活。靶向治疗RASH3D19有望在表达KRAS的突变型癌症中导致肿瘤缩小并减轻对KRAS抑制剂的耐药性。

据了解，目前正在积极研究驱动癌症的突变KRAS通路的治疗靶向，以确定对正在进行临床试验的突变KRAS抑制剂产生适应性耐药的反馈机制。

附：英文原文

Title: RASH3D19 mediates RAS activation through a positive feedback loop in KRAS-mutant cancer

Author: Treekitkarnmongkol, Warapen, Katayama, Hiroshi, Sankaran, Deivendran, Tai, Mei-Chee, Rauth, Sanchita, Chen, Hanxiao, Nguyen, Tristian, Hara, Kieko, Thege, Fredrik I., Ponnusamy, Moorthy P., Batra, Surinder K., Wang, Huamin, Wistuba, Ignacio I., Schmittgen, Thomas D., Heymach, John V., Kopetz, Scott, Hu, Tony, Yao, Wantong, Maitra, Anirban, Sen, Subrata

Issue&Volume: 2025-12-01

Abstract: Therapeutic targeting of mutant KRAS pathways driving cancers is being actively investigated to identify feedback mechanisms responsible for the development of adaptive resistance to mutant KRAS inhibitors undergoing clinical trials. Here we report RASH3D19 as a mediator of RAS pathway activation through a positive feedback loop involving the KRAS–microRNA signalling axis. KRAS-induced miR-222 represses ETS1 expression and downstream transactivation of miR-301a leading to elevation of its target RASH3D19. RASH3D19 facilitates activation of RAS pathways by promoting dimerization and interaction of EGFR with the SOS2, GRB2, SHP2 and GAB1 complex. Genetic deletion of RASH3D19 in mutant KRAS-expressing cancer cells exhibits growth retardation in vitro, in vivo and sensitized pancreatic ductal adenocarcinoma and colorectal cancer cells, organoids and xenografts to mutant KRAS inhibitors, suppressing feedback reactivation of RAS pathways. Therapeutic targeting of RASH3D19 is expected to lead to tumour debulking and alleviating resistance to KRAS inhibitors in mutant KRAS-expressing cancers.

DOI: 10.1038/s41556-025-01816-5

Source: https://www.nature.com/articles/s41556-025-01816-5