近日，美国北卡罗来纳大学教授Chad V. Pecot及其研究团队报道了一种一流的EGFR定向KRAS G12V选择性抑制剂。相关论文发表在2025年6月19日出版的《癌细胞》杂志上。

在这项研究中，该研究团队证明了egfr导向的RNAi分子（EFTX-G12V）对KRASG12V具有高度选择性，并且比pan-KRAS靶向表现出更好的治疗活性，包括增强对几种癌症标志的抑制。利用靶向RNAi传递平台，小组实现了KRASG12V的有效肿瘤沉默和多种癌症模型的显著抗肿瘤活性。他们的发现代表了癌基因靶向主题化RNAi的技术进步，并为KRAS靶向提供了新的生物学见解，具有潜在的安全性和有效性。

据悉，尽管KRASG12V是癌症中第二常见的KRAS突变，但目前还没有针对KRASG12V的直接抑制剂被批准。RNA干扰（RNAi）在癌症治疗中面临许多障碍，包括缺乏癌症特异性组织靶向，快速寡核苷酸核酸酶降解以及从循环中清除。最近，靶向配体与化学修饰的siRNAs结合的主题在绕过这些障碍方面显示出显着的希望。

附：英文原文

Title: A first-in-class EGFR-directed KRAS G12V selective inhibitor

Author: Lyla J. Stanland, Hayden P. Huggins, Snehasudha S. Sahoo, Alessandro Porrello, Yogitha Chareddy, Salma H. Azam, Jillian L. Perry, Pradeep S. Pallan, Kristina Whately, Lincy Edatt, William D. Green, Matthew C. Fleming, Jonah Im, Christina Gutierrez-Ford, Imani Simmons, Alyaa Dawoud, Katherine I. Zhou, Vandanaa Jayaprakash, Rani S. Sellers, Gabriela de la Cruz, Albert Wielgus, Justin Milner, Martin Egli, Albert A. Bowers, Chad V. Pecot

Issue&Volume: 2025-06-19

Abstract: Despite KRASG12V being the second most common KRAS mutation in cancer, no direct inhibitors targeting KRASG12V 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 KRASG12V 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 KRASG12V 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.

DOI: 10.1016/j.ccell.2025.05.016

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00225-9