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

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-06-19 DOI:10.1016/j.ccell.2025.05.016

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, Chad V. Pecot

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引用次数: 0

Abstract

Despite KRAS^G12V being the second most common KRAS mutation in cancer, no direct inhibitors targeting KRAS^G12V 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^G12V 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^G12V 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.

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一种一流的egfr定向KRAS G12V选择性抑制剂

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，使用靶向配体偶联到化学修饰的sirna在绕过这些障碍方面显示出显着的希望。在这项研究中，我们证明了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，我们实现了KRASG12V的有效肿瘤沉默和多种癌症模型的显著抗肿瘤活性。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，具有潜在的安全性和有效性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.