Stanland Lyla J, Huggins Hayden P, Sahoo Snehasudha S, Porrello Alessandro, Chareddy Yogitha, Azam Salma H, Perry Jillian L, Pallan Pradeep S, Whately Kristina, Edatt Lincy, Green William D, Fleming Matthew C, Im Jonah, Gutierrez-Ford Christina, Simmons Imani, Dawoud Alyaa, Zhou Katherine I, Jayaprakash Vandanaa, Sellers Rani S, Cruz Gabriela de la, Wielgus Albert, Milner Justin, Egli Martin, Bowers Albert A, Pecot Chad V
EnFuego Therapeutics, Inc, Morrisville, NC 27560, USA.
EnFuego Therapeutics, Inc, Morrisville, NC 27560, USA; Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA.
Cancer Cell. 2025 Jun 16. doi: 10.1016/j.ccell.2025.05.016.
Despite KRAS being the second most common KRAS mutation in cancer, no direct inhibitors targeting KRAS have been approved. RNA interference (RNAi) has faced numerous obstacles as cancer therapeutic, including the lack of cancer-specific tissue targeting, rapid oligonucleotide nuclease degradation, and clearance from circulation. Recently, the use of targetable ligands conjugated to chemically modified siRNAs have shown remarkable promise in circumventing these barriers. In this study, we demonstrate that an EGFR-directed RNAi molecule (EFTX-G12V) is highly selective for KRAS and exhibits improved therapeutic activity over pan-KRAS targeting, including enhanced inhibition of several cancer hallmarks. Using a targeted RNAi delivery platform, we achieve effective tumor silencing of KRAS and significant anti-tumor activity across several cancer models. Our findings represent a technological advance in oncogene targeting using RNAi and provide new biologic insights in KRAS targeting with potential implications for safety and efficacy.
尽管KRAS是癌症中第二常见的KRAS突变，但尚无针对KRAS的直接抑制剂获批。RNA干扰（RNAi）作为癌症治疗手段面临诸多障碍，包括缺乏癌症特异性组织靶向性、寡核苷酸快速被核酸酶降解以及从循环中清除。最近，将可靶向配体与化学修饰的小干扰RNA（siRNA）偶联使用在克服这些障碍方面显示出显著前景。在本研究中，我们证明一种表皮生长因子受体（EGFR）导向的RNAi分子（EFTX-G12V）对KRAS具有高度选择性，并且与泛KRAS靶向相比具有更高的治疗活性，包括增强对多种癌症特征的抑制作用。使用靶向RNAi递送平台，我们在多种癌症模型中实现了KRAS的有效肿瘤沉默和显著的抗肿瘤活性。我们的研究结果代表了使用RNAi靶向癌基因的技术进步，并为KRAS靶向提供了新的生物学见解，对安全性和有效性可能具有潜在影响。
