Reprogramming Tumor-Associated Macrophages To Reverse EGFRT790M Resistance by Dual-Targeting Codelivery of Gefitinib/Vorinostat.

Abstract

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. EGFRT790M mutation is the major cause responsible for the molecular-targeting therapy failure in NSCLC. Although the recently approved osimertinib is effective for the EGFRT790M-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 EGFRT790M-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 EGFRT790M degradation through 790M oxidation by ROS, thus resensitizing the EGFRT790M-positive cells to gefitinib. The dual-targeting codelivery and TAM-reprogramming strategies provided a potential method for rescuing the EGFRT790M-caused resistance to tyrosine kinase inhibitor treatment.

• Authors: Huige Peng, Binfan Chen, Wei Huang, Yubo Tang, Yifan Jiang, Wenyuan Zhang, Yongzhuo Huang
• Journal: Nano letters (Nano Lett) Vol. 17 Issue 12 Pg. 7684-7690 (12 13 2017) ISSN: 1530-6992 [Electronic] United States
• PMID: 29160717 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acrylamides
• Aniline Compounds
• Drug Carriers
• Lectins, C-Type
• Liposomes
• Mannose Receptor
• Mannose-Binding Lectins
• Piperazines
• Receptors, Cell Surface
• osimertinib
• Vorinostat
• ErbB Receptors
• Gefitinib

Topics

• Acrylamides
• Aniline Compounds
• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, chemistry, pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Drug Carriers (chemistry)
• Drug Liberation
• Drug Resistance, Neoplasm (drug effects)
• ErbB Receptors (genetics)
• Gefitinib (administration & dosage, chemistry, pharmacology)
• Humans
• Lectins, C-Type (metabolism)
• Liposomes (chemistry)
• Lung Neoplasms (drug therapy, pathology)
• Macrophages (drug effects, pathology)
• Mannose Receptor
• Mannose-Binding Lectins (metabolism)
• Mice
• Mutation
• Piperazines (pharmacology)
• Receptors, Cell Surface (metabolism)
• Vorinostat (administration & dosage, chemistry, pharmacology)