Shen Song, Mao Chong-Qiong, Yang Xian-Zhu, Du Xiao-Jiao, Liu Yang, Zhu Yan-Hua, Wang Jun
School of Life Sciences and ‡Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China , Hefei, Anhui 230027, P. R. China.
Mol Pharm. 2014 Aug 4;11(8):2612-22. doi: 10.1021/mp400714z. Epub 2014 Feb 20.
Synthetic lethal interaction provides a conceptual framework for the development of wiser cancer therapeutics. In this study, we exploited a therapeutic strategy based on the interaction between GATA binding protein 2 (GATA2) downregulation and the KRAS mutation status by delivering small interfering RNA targeting GATA2 (siGATA2) with cationic lipid-assisted polymeric nanoparticles for treatment of non-small-cell lung carcinoma (NSCLC) harboring oncogenic KRAS mutations. Nanoparticles carrying siGATA2 (NPsiGATA2) were effectively taken up by NSCLC cells and resulted in targeted gene suppression. NPsiGATA2 selectively inhibited cell proliferation and induced cell apoptosis in KRAS mutant NSCLC cells. However, this intervention was harmless to normal KRAS wild-type NSCLC cells and HL7702 hepatocytes, confirming the advantage of synthetic lethality-based therapy. Moreover, systemic delivery of NPsiGATA2 significantly inhibited tumor growth in the KRAS mutant A549 NSCLC xenograft murine model, suggesting the therapeutic promise of NPsiGATA2 delivery in KRAS mutant NSCLC therapy.
合成致死相互作用为开发更明智的癌症治疗方法提供了一个概念框架。在本研究中，我们通过用阳离子脂质辅助聚合物纳米颗粒递送靶向GATA结合蛋白2（GATA2）的小干扰RNA（siGATA2），利用基于GATA2下调与KRAS突变状态之间相互作用的治疗策略，来治疗携带致癌KRAS突变的非小细胞肺癌（NSCLC）。携带siGATA2的纳米颗粒（NPsiGATA2）被NSCLC细胞有效摄取，并导致靶向基因抑制。NPsiGATA2选择性抑制KRAS突变NSCLC细胞的增殖并诱导细胞凋亡。然而，这种干预对正常KRAS野生型NSCLC细胞和HL7702肝细胞无害，证实了基于合成致死性疗法的优势。此外，NPsiGATA2的全身递送显著抑制了KRAS突变A549 NSCLC异种移植小鼠模型中的肿瘤生长，表明NPsiGATA2递送在KRAS突变NSCLC治疗中的治疗前景。
