Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing...

Area of Science:

• Oncology
• Nanomedicine
• Pharmacology

Background:

• Osimertinib (Osi) is a first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC).
• High rates of patient relapse due to Osi resistance necessitate novel therapeutic strategies.
• Mechanisms underlying Osi resistance are not fully understood.

Purpose of the Study:

• To develop a lactoferrin-modified liposomal codelivery system for Osi and panobinostat (Pan).
• To investigate the efficacy of this combination therapy in overcoming Osi resistance in NSCLC.
• To explore the underlying mechanisms of action, including effects on tumor microenvironment and drug resistance pathways.

Main Methods:

• Development of a lactoferrin-modified liposomal system for codelivering Osi and Pan.
• In vitro and in vivo studies to evaluate the therapeutic efficacy and mechanisms.
• Assessment of tumor-associated macrophage (TAM) repolarization (M2 to M1).
• Evaluation of epithelial-mesenchymal transition (EMT) reversal and suppression of glycolysis, lactic acid production, and angiogenesis.

Main Results:

• The liposomal codelivery system efficiently delivered both Osi and Pan.
• The combination therapy successfully repolarized TAMs from M2 to M1 phenotype.
• Epithelial-mesenchymal transition (EMT)-associated drug resistance was reversed, and tumor cell glycolysis, lactic acid production, and angiogenesis were suppressed.
• Significant therapeutic effects were observed in overcoming Osi resistance in NSCLC models.

Conclusions:

• Liposomal codelivery of Osi and Pan is a potent strategy to overcome Osi resistance in NSCLC.
• The therapy modulates the tumor microenvironment and reverses key resistance mechanisms.
• This approach holds promise for improving clinical outcomes in NSCLC patients resistant to Osi treatment.