Multieffect Specific Nanovesicles for Homing Resistant Tumors and Overcoming Osimertinib-Acquired Resistance in NSCLC

Area of Science:

• Oncology
• Materials Science
• Nanotechnology

Background:

• Acquired resistance to osimertinib (Osi) is a significant challenge in treating EGFR-mutant non-small cell lung cancer (NSCLC).
• AXL receptor tyrosine kinase (RTK) upregulation and elevated intracellular glutathione (GSH) are identified as key mechanisms driving Osi resistance.
• Current therapeutic strategies to overcome this resistance are limited.

Purpose of the Study:

• To elucidate the novel mechanism by which GSH regulates AXL expression via glutathione peroxidase 4 (GPX4) in Osi-resistant NSCLC cells.
• To design and construct a multifunctional nanoplatform for simultaneous targeting of GSH and AXL pathways to restore Osi sensitivity.
• To evaluate the efficacy of this nanoplatform in overcoming Osi resistance both in vitro and in vivo.

Main Methods:

• A multifunctional covalent organic framework (COF) nanoplatform was engineered for GSH consumption and AXL inhibition.
• The COF nanoplatform was designed for co-delivery of Osi and an AXL inhibitor (Brigatinib).
• The nanoplatform was surface-functionalized with specific vesicles for targeted delivery to CDH2-expressing resistant tumors.

Main Results:

• The engineered nanovesicles effectively inhibited the GSH-AXL signaling axis in Osi-resistant cells.
• The nanoplatform demonstrated significant induction of apoptosis in Osi-resistant NSCLC cells.
• In vivo studies showed that the nanovesicles delayed the progression of Osi-resistant tumors.

Conclusions:

• A novel GSH-GPX4-AXL regulatory axis contributing to Osi resistance in NSCLC was identified.
• A multifunctional nanovesicle system offers a promising strategy to overcome acquired resistance to osimertinib by simultaneously targeting GSH and AXL.
• This approach holds potential for improving treatment outcomes in patients with EGFR-mutant NSCLC who develop acquired resistance.