Discovery in RNA therapy for mutated cancer gene

Two complementary studies led by researchers from the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), have demonstrated a new RNA-based therapeutic strategy that effectively targets one of the most difficult-to-treat cancer genes, Kirsten rat sarcoma viral oncogene homolog (KRAS), while stimulating the body’s immune response to fight tumours. The research was conducted in cell samples and laboratory models, with collaborators from the NUS Institute for Health Innovation and Technology (iHealthtech), Nanyang Technological University (NTU), Agency for Science, Technology and Research (A*STAR), and international partners.

KRAS is a gene that acts like a molecular switch controlling how cells grow and divide. In healthy cells, this switch turns on and off as needed. However, in many cancers, including pancreatic, lung, and colorectal cancers, the KRAS gene becomes mutated, locking the switch in the “on” position. This constant activation drives uncontrolled cell growth and helps tumours evade normal immune defences. Mutations in KRAS are among the most common drivers of human cancers and are found in over 90% of pancreatic cancers[1]. As the KRAS protein binds tightly to its signalling molecules and lacks easy-to-target binding sites, it has long been considered “undruggable” — making it one of the toughest and most important targets in cancer research.

The research team developed a combination therapy using antisense oligonucleotides (ASOs) to silence mutant KRAS genes and an immunomodulatory RNA (immRNA) that activates the Retinoic acid-Inducible Gene I (RIG-I) immune pathway. The RIG-I pathway is akin to an alarm system in our cells, where it detects viruses and then alerts our immune system to deal with the threat. Both the ASOs and immRNA molecules were delivered safely using red blood cell-derived extracellular vesicles (RBCEVs), a natural, biocompatible carrier for nucleic acid drugs.

In the first study, published in Theranostics, the researchers showed that the combined ASO–immRNA treatment killed KRAS-mutant cancer cells—including lung, colorectal, and pancreatic cancers—by simultaneously blocking oncogenic KRAS activity and triggering antiviral-like immune signalling. The dual treatment converted “cold” tumours that typically evade immune attack into “hot” ones that the immune system can recognise and attack, reducing tumour burden and extending survival in laboratory studies without harming normal cells.

Building on these results, the second study, published in the Journal of Controlled Release on Science Direct, advanced the therapy to the preclinical stage for pancreatic cancer, primarily pancreatic ductal adenocarcinoma (PDAC), with peritoneal metastasis. PDAC is one of the deadliest forms of cancer, with a 5-year survival rate of 10%[2]. However, the treatment markedly suppressed tumour growth, limited abdominal spread, and prolonged survival in laboratory studies. Importantly, safety testing showed no observable toxicity in laboratory studies, supporting its potential for future clinical evaluation.

“KRAS mutations hijack cancer cells and suppress immune responses, enabling metastasis,” said Associate Professor Minh Le, Department of Pharmacology, and Institute for Digital Medicine (WisDM), NUS Medicine, “Our EV platform precisely targets mutants, sparing healthy tissue, and synergises KRAS knockdown with RIG-I activation to unleash interferons, immunogenic cell death, and T-cell memory—halting tumour growth and extending survival without toxicity.”

Associate Professor Glenn Bonney, Senior Consultant, Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, National University Hospital (NUH), who contributed patient-derived organoids for the studies, added, “This dual nucleic acid delivery via biocompatible vesicles overcomes KRAS resistance barriers, offering a safe, scalable path to treat peritoneal metastasis—a major unmet need in PDAC.”

Professor Dahai Luo, from NTU's Lee Kong Chian School of Medicine and co-author of the papers, added, “By engineering EVs for targeted delivery, we have turned natural cell messengers into precision weapons, with broad potential for other KRAS-addicted cancers like colorectal and lung.”

Adjunct Professor Jonathan Loh Yuin-Han, Deputy Executive Director (Research) at the Institute of Molecular and Cell Biology (IMCB), A*STAR and co-author of one publication, said, “This innovative combination of KRAS-targeting ASOs and RIG-I agonists delivered via extracellular vesicles reprograms the tumour microenvironment, charting a new path toward transforming KRAS-driven cancers and bringing us closer to effective, personalised immunotherapies with the potential to save lives and revolutionise cancer treatment.”

The research highlights the growing potential of extracellular vesicles as safe and versatile carriers for nucleic acid-based therapies. Beyond pancreatic cancer, the platform may be adapted to other KRAS-driven malignancies and combined with existing immunotherapies to improve treatment outcomes.

[1] S.B. Dreyer, D.K. Chang, P. Bailey, A.V. Biankin, Pancreatic cancer genomes: implications for clinical management and therapeutic development, Clin. Cancer Res. 23 (7) (2017) 1638–1646, https://doi.org/10.1158/1078-0432.

[2] H. Ying, P. Dey, W. Yao, et al., Genetics and biology of pancreatic ductal adenocarcinoma, Genes Dev. 30 (4) (2016) 355–385, https://doi.org/10.1101/ gad.275776.115.