1 research outputs found
Reprogramming Tumor-Associated Macrophages To Reverse EGFR<sup>T790M</sup> Resistance by Dual-Targeting Codelivery of Gefitinib/Vorinostat
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<sup>T790M</sup> mutation is the major cause responsible for the molecular-targeting
therapy failure in NSCLC. Although the recently approved osimertinib
is effective for the EGFR<sup>T790M</sup>-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<sup>T790M</sup>-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<sup>T790M</sup> degradation through 790M
oxidation by ROS, thus resensitizing the EGFR<sup>T790M</sup>-positive
cells to gefitinib. The dual-targeting codelivery and TAM-reprogramming
strategies provided a potential method for rescuing the EGFR<sup>T790M</sup>-caused resistance to tyrosine kinase inhibitor treatment