Singapore Researchers Develop RNA Therapy Targeting "Undruggable" KRAS Cancer Gene
核心洞察
Researchers from NUS Medicine (搜索) have developed a dual RNA-based therapy that effectively targets KRAS (搜索) mutations, found in over 90% of pancreatic cancers and long considered "undruggable."
The combination treatment uses antisense oligonucleotides to silence mutant KRAS (搜索) genes and immunomodulatory RNA (搜索) to activate immune responses, delivered via red blood cell-derived extracellular vesicles.
Preclinical studies showed the therapy converted "cold" tumors into "hot" ones recognizable by the immune system, markedly suppressing tumor growth and extending survival without observable toxicity.
Researchers from the National University of Singapore have achieved a significant breakthrough in targeting one of cancer's most elusive therapeutic targets, developing a novel RNA-based combination therapy that effectively attacks KRAS (搜索) mutations while simultaneously boosting immune responses against tumors. The dual approach addresses a longstanding challenge in oncology, as KRAS mutations drive some of the most aggressive and treatment-resistant cancers.
Targeting the "Undruggable" KRAS Gene
KRAS (搜索) functions as a molecular switch controlling cellular growth and division, operating normally in healthy cells by turning on and off as needed. However, in many cancers including pancreatic, lung, and colorectal malignancies, KRAS becomes mutated and locked in the "on" position, driving uncontrolled cell growth and helping tumors evade immune defenses. These mutations represent among the most common drivers of human cancers, appearing in over 90% of pancreatic cancers.
The KRAS (搜索) protein has earned its reputation as "undruggable" due to its tight binding to signaling molecules and lack of easily targetable binding sites, making it one of the most challenging and important targets in cancer research.
Dual-Action Therapeutic Strategy
The research team, led by scientists from the Yong Loo Lin School of Medicine at NUS, developed a combination therapy utilizing two complementary mechanisms. The approach employs antisense oligonucleotides (ASOs (搜索)) to silence mutant KRAS (搜索) genes alongside immunomodulatory RNA (搜索) (immRNA (搜索)) that activates the Retinoic acid-Inducible Gene I (RIG-I (搜索)) immune pathway.
The RIG-I (搜索) pathway functions as a cellular alarm system, detecting viral threats and alerting the immune system to respond. Both therapeutic molecules are delivered using red blood cell-derived extracellular vesicles (RBCEVs), which serve as natural, biocompatible carriers for nucleic acid drugs.
Converting Cold Tumors to Hot
In the first study published in Theranostics, researchers demonstrated that the combined ASO-immRNA (搜索) treatment effectively killed KRAS (搜索)-mutant cancer cells across multiple cancer types, including lung, colorectal, and pancreatic cancers. The therapy works by simultaneously blocking oncogenic KRAS activity and triggering antiviral-like immune signaling.
Critically, the dual treatment converted "cold" tumors that typically evade immune attack into "hot" ones that the immune system can recognize and attack. This transformation reduced tumor burden and extended survival in laboratory studies without harming normal cells.
Advancing to Pancreatic Cancer Treatment
Building on these promising results, a second study published in the Journal of Controlled Release advanced the therapy to preclinical testing specifically for pancreatic cancer (搜索), focusing on pancreatic ductal adenocarcinoma (搜索) (PDAC (搜索)) with peritoneal metastasis. PDAC represents one of cancer's deadliest forms, with a five-year survival rate of just 10%.
The treatment demonstrated remarkable efficacy, markedly suppressing tumor growth, limiting abdominal spread, and prolonging survival in laboratory studies. Importantly, safety testing revealed no observable toxicity, supporting the therapy's potential for future clinical evaluation.
Expert Perspectives on Clinical Impact
"KRAS (搜索) mutations hijack cancer cells and suppress immune responses, enabling metastasis," explained Associate Professor Minh Le from NUS Medicine (搜索)'s Department of Pharmacology. "Our EV platform precisely targets mutants, sparing healthy tissue, and synergizes KRAS knockdown with RIG-I (搜索) activation to unleash interferons, immunogenic cell death, and T-cell memory—halting tumor growth and extending survival without toxicity."
Associate Professor Glenn Bonney, who contributed patient-derived organoids for the studies, emphasized the clinical significance: "This dual nucleic acid delivery via biocompatible vesicles overcomes KRAS (搜索) resistance barriers, offering a safe, scalable path to treat peritoneal metastasis—a major unmet need in PDAC (搜索)."
Broader Therapeutic Potential
The research highlights the growing potential of extracellular vesicles as versatile carriers for nucleic acid-based therapies. Professor Dahai Luo from NTU noted the platform's broader applications: "By engineering EVs for targeted delivery, we have turned natural cell messengers into precision weapons, with broad potential for other KRAS (搜索)-addicted cancers like colorectal and lung."
The platform may be adapted to other KRAS (搜索)-driven malignancies and combined with existing immunotherapies to improve treatment outcomes. As Adjunct Professor Jonathan Loh from A*STAR (搜索) observed, "This innovative combination of KRAS-targeting ASOs (搜索) and RIG-I (搜索) agonists delivered via extracellular vesicles reprograms the tumor microenvironment, charting a new path toward transforming KRAS-driven cancers and bringing us closer to effective, personalized immunotherapies with the potential to save lives and revolutionize cancer treatment."