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

Nat Cell Biol. 2025 Dec 1. doi: 10.1038/s41556-025-01816-5.

Warapen Treekitkarnmongkol ^# ¹, Hiroshi Katayama ^# ², Deivendran Sankaran ^# ¹ ³, Mei-Chee Tai ¹ ⁴, Sanchita Rauth ⁵, Hanxiao Chen ⁶, Tristian Nguyen ¹, Kieko Hara ¹, Fredrik I Thege ¹ ⁷, Moorthy P Ponnusamy ⁵, Surinder K Batra ⁵, Huamin Wang ⁸, Ignacio I Wistuba ¹ ⁹ ¹⁰, Thomas D Schmittgen ¹¹, John V Heymach ¹², Scott Kopetz ¹³, Tony Hu ¹⁴, Wantong Yao ¹, Anirban Maitra ¹ ⁷ ⁸ ⁹ ¹⁵, Subrata Sen ¹⁶ ¹⁷

Affiliations

1 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
3 Signal Transduction and Molecular Pharmacology, Centre for Cancer Drug Discovery, The Institute of Cancer Research London, London, UK.
4 Cancer Research Malaysia, Subang Jaya, Malaysia.
5 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
6 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, and Oncode Institute, UMC Utrecht, Utrecht, the Netherlands.
7 Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
9 The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
10 Department of Translational Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tempa, FL, USA.
11 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
12 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
13 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
14 Center for Cellular and Molecular Diagnostics, Department of Molecular and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
15 GI Cancer Center, NYU Langone Health Perlmutter Cancer Center, New York, NY, USA.
16 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
17 The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. [email protected].
# Contributed equally.

PMID: 41326795 DOI: 10.1038/s41556-025-01816-5

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-114277

Sotorasib

99.70%, KRAS G12C Inhibitor

Ras

Cancer
HY-116009

RMC-4550

99.56%, SHP2 Inhibitor

SHP2; Phosphatase

Cancer

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