Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
University of Chinese Academy of Sciences , Beijing 100049, China.
Nano Lett. 2017 Dec 13;17(12):7684-7690. doi: 10.1021/acs.nanolett.7b03756. Epub 2017 Nov 21.
Gefitinib is a first-line therapy in the EGFR-mutated nonsmall cell lung cancer (NSCLC). However, the development of drug resistance is almost unavoidable, thus leading to an unsustainable regimen. EGFR mutation is the major cause responsible for the molecular-targeting therapy failure in NSCLC. Although the recently approved osimertinib is effective for the EGFR-positive NSCLC, the osimertinib-resistant EGFR mutation is rapidly developed, too. In this study, we proposed a tumor-associated macrophage (TAM) reprogramming strategy for overcoming the EGFR-associated drug resistance via a dual-targeting codelivery system of gefitinib/vorinostat that acted on both TAM with overexpression of mannose receptors and the HER-2 positive NSCLC cells. The trastuzumab-modified, mannosylated liposomal system was able to repolarize the protumor M2 phenotype to the antitumor M1 and cause the elevating ROS in the cancer cells, consequently modulating the intracellular redox balance via ROS/NOX3/MsrA axis. The suppressed MsrA facilitated the EGFR degradation through 790M oxidation by ROS, thus resensitizing the EGFR-positive cells to gefitinib. The dual-targeting codelivery and TAM-reprogramming strategies provided a potential method for rescuing the EGFR-caused resistance to tyrosine kinase inhibitor treatment.
吉非替尼是 EGFR 突变型非小细胞肺癌（NSCLC）的一线治疗药物。然而，几乎不可避免地会出现耐药性的发展，从而导致治疗方案无法持续。EGFR 突变是 NSCLC 分子靶向治疗失败的主要原因。尽管最近批准的奥希替尼对 EGFR 阳性 NSCLC 有效，但奥希替尼耐药的 EGFR 突变也迅速发展。在这项研究中，我们提出了一种肿瘤相关巨噬细胞（TAM）重编程策略，通过吉非替尼/伏立诺他的双重靶向递药系统克服 EGFR 相关耐药性，该系统作用于高表达甘露糖受体的 TAM 和 HER-2 阳性 NSCLC 细胞。曲妥珠单抗修饰的甘露糖化脂质体系统能够将促肿瘤 M2 表型重新极化为抗肿瘤 M1，并在癌细胞中引起 ROS 升高，从而通过 ROS/NOX3/MsrA 轴调节细胞内氧化还原平衡。抑制 MsrA 通过 ROS 促进 790M 氧化，从而使 EGFR 阳性细胞对吉非替尼重新敏感。双重靶向递药和 TAM 重编程策略为挽救酪氨酸激酶抑制剂治疗引起的 EGFR 耐药提供了一种潜在的方法。
