Researchers at The University of Texas MD Anderson Cancer Center have identified a specific protein, RASH3D19, that is responsible for activation of RAS signaling pathways involved in aggressive tumor growth and resistance to KRAS inhibitors in patients with KRAS-mutant cancers. Blocking RASH3D19 in combination with KRAS inhibitors improved outcomes in preclinical models, suggesting this combination as a potential therapeutic strategy for patients with KRAS-mutant cancers.

The study, published in Nature Cell Biology, was led by Subrata Sen, Ph.D., deputy chair of Translational Molecular Pathology, and Hiroshi Katayama, Ph.D., associate professor of Translational Molecular Pathology, along with co-first authors, Warapen Treekitkarnmongkol, Ph.D., and Deivendran Sankaran, Ph.D.

"These findings provide crucial clarity on the mechanisms of RAS pathway activation, identify an actionable target responsible for aggressive disease in patients with KRAS-mutant cancers, and provide insights into the development of resistance to KRAS-targeting drugs. This has significant clinical implications that can, hopefully, improve outcomes for patients," Sen said.

Many patients with KRAS-mutant cancers, such as pancreatic, lung and colon cancers, who are treated with KRAS-targeting drugs eventually develop resistance to these therapies. This is usually due to re-activation of the RAS signaling pathway, which drives tumor growth.

Cancer cells find ways to activate the pathway either by acquiring additional KRAS mutations or by activating other components of the pathway. In this study, researchers identified a key upstream component activating the pathway through a positive feedback mechanism.

The RASH3D19 protein, specifically, acts as a booster to activate the RAS signaling pathway, promoting tumor growth and treatment resistance. Activated RAS then also promotes elevated expression of RASH3D19, creating a positive feedback loop. Reducing levels of RASH3D19 downregulated the RAS pathway and slowed tumor growth. Conversely, overexpression of RASH3D19 hyperactivates the feedback loop and promotes treatment resistance.

Using both RASH3D19 silencing and KRAS inhibitors worked better in lab models than either one alone.

This study shows that RASH3D19 silencing sensitizes cancer cells to RAS inhibitors in preclinical models, suggesting that it could work well in combination with KRAS inhibitors as a strategy to overcome treatment resistance in patients with KRAS-mutant cancers.

Future clinical trials are needed to explore the potential benefits for patients with similar combinations.

Treekitkarnmongkol W, Katayama H, Sankaran D, Tai MC, Rauth S, Chen H, Nguyen T, Hara K, Thege FI, Ponnusamy MP, Batra SK, Wang H, Wistuba II, Schmittgen TD, Heymach JV, Kopetz S, Hu T, Yao W, Maitra A, Sen S.
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