A Novel siRNA Selectively Targets And Inhibits KRAS G12V Mutation in Tumors

Missense mutations in the KRAS gene often lead to its persistent activation, which in turn causes dysregulation of downstream signaling cascades and drives tumorigenesis. KRAS gene mutations are present in nearly 25% of human cancers and are frequently found in some of the most common cancer types, such as lung cancer (35%), colorectal cancer (49%), and pancreatic adenocarcinoma (92%).

Among all KRAS gene mutations, KRAS^G12D, KRAS^G12V, and KRAS^G12C are the most common, accounting for 29%, 23%, and 15%, respectively. KRAS has always been considered a difficult drug target, until recently two small molecule inhibitors were approved for marketing, namely sotorasib and adagrasib, both of which target KRAS^G12C. This also means that more KRAS gene mutations are still unavailable. Therefore, there is an urgent need to develop specific inhibitors that can target mutations other than KRAS^G12C.

Recently, EnFuego and researchers from the University of North Carolina at Chapel Hill collaborated to publish a research paper titled "A first-in-class EGFR-directed KRAS G12V selective inhibitor" in the Cell journal Cancer Cell. The study developed a first-in-class EGFR-directed siRNA drug that selectively targets and inhibits a common KRAS gene mutation type in tumors, KRAS^G12V.

Figure 1. EFTX-G12V is a highly potent mutant-selective siRNA inhibitor of KRAS G12V. (Stanland, Lyla J., et al. 2025).

Although KRAS^G12V is the second most common type of KRAS gene mutation in cancer, there are currently no approved inhibitors that directly target KRAS^G12V. Since 2018, the US FDA has approved seven RNA interference (RNAi)-based siRNA drugs for the treatment of rare diseases and diseases such as hypercholesterolemia. However, there are currently no approved RNAi drugs for cancer treatment. Its use in cancer treatment faces many obstacles - including lack of specific targeting of cancer tissues, oligonucleotides are easily degraded by nucleases, and are quickly cleared in the blood circulation. In recent years, methods that couple targeting ligands to chemically modified siRNAs have shown significant promise in overcoming the above obstacles.

Considering that epidermal growth factor receptor (EGFR) is highly expressed in many types of cancer, the research team coupled the EGFR binding peptide (GE11C) with siRNA that specifically targets KRAS^G12V to construct an EGFR-guided, highly specific RNAi molecule, EFTX-G12V. It is able to specifically target cancer cells and inhibit the expression of KRAS^G12V, and is superior to pan-KRAS siRNA in terms of therapeutic activity, with a stronger cancer inhibition effect (which suggests that non-mutated KRAS genes may have anti-tumor effects). Using a targeted RNAi delivery platform, the research team achieved effective silencing of KRAS^G12V in a variety of cancer models and achieved significant anti-tumor activity.

The research team said that the technology is highly modular and can theoretically target and inhibit almost any oncogene by simply replacing the siRNA sequence. In addition, this two-in-one model can also help overcome drug resistance and enhance the durability of therapeutic effects. Overall, this study represents a major technological advancement in RNAi-based siRNA drugs in targeting oncogene mutations, providing new biological insights into KRAS targeted therapy and having broader clinical significance in terms of drug toxicity and therapeutic effects.