TY - JOUR
T1 - RASH3D19 mediates RAS activation through a positive feedback loop in KRAS-mutant cancer
AU - Treekitkarnmongkol, Warapen
AU - Katayama, Hiroshi
AU - Sankaran, Deivendran
AU - Tai, Mei Chee
AU - Rauth, Sanchita
AU - Chen, Hanxiao
AU - Nguyen, Tristian
AU - Hara, Kieko
AU - Thege, Fredrik I.
AU - Ponnusamy, Moorthy P.
AU - Batra, Surinder K.
AU - Wang, Huamin
AU - Wistuba, Ignacio I.
AU - Schmittgen, Thomas D.
AU - Heymach, John V.
AU - Kopetz, Scott
AU - Hu, Tony
AU - Yao, Wantong
AU - Maitra, Anirban
AU - Sen, Subrata
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2025.
PY - 2026
Y1 - 2026
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105023533820
U2 - 10.1038/s41556-025-01816-5
DO - 10.1038/s41556-025-01816-5
M3 - Article
C2 - 41326795
AN - SCOPUS:105023533820
SN - 1465-7392
VL - 28
SP - 197
EP - 206
JO - Nature Cell Biology
JF - Nature Cell Biology
ER -