Lung cancer is the leading cause of cancer related deaths worldwide and second commonly diagnosed cancer among men and women. Epidermal growth factor receptor (EGFR) is frequently dysregulated in lung cancers and has been implicated in pathogenesis of this disease. Because of this, EGFR-tyrosine kinase inhibitors (TKIs) have since been developed as a primary form of treatment. However, many patients do not initially respond, or they inevitably develop resistance to EGFR-TKIs within 12-14 months of treatment. Therefore, discovering new drugs for these patients is increasingly important. We found that silver nanoparticles (AgNPs) are effective for the treatment of inherent and acquired resistance to EGFR-TKI in lung cancer cells. We establish that doses of AgNPs that are highly cytotoxic to EGFR-TKI resistant lung cancers are non-toxic to non-malignant lung cells. No differences were observed in the internalization or intracellular trafficking of AgNPs in AgNP sensitive cells and AgNP resistant cells, indicating that the difference in sensitivity was not due to the quantity of AgNPs internalized. Therefore, we performed mechanistic studies to identify the underlying biology of the cells that was responsible for this difference. We observed that AgNPs induce lipid peroxidation, protein oxidation and aggregation in EGFR-TKI resistant lung cancers. This then leads to irremediable endoplasmic reticulum (ER) stress, resulting in cell death. In contrast, doses of AgNPs that were lethal to EGFR-TKI resistant cancers had no effect on EGFR-TKI sensitive lung cancers. We further establish that EGFR-TKI resistant lung cancers exhibit increased expression of extracellular matrix proteins including fibronectin and collagen. Knockdown of fibronectin in EGFR-TKI resistant cells decreases their sensitivity to AgNPs by reducing baseline endoplasmic reticulum stress. This work provides a rationale for the development of AgNPs for the treatment of EGFR-TKI resistant lung cancer.<br/>

Production of fibronectin sensitizes EGFR-TKI resistant lung cancers to silver nanoparticle induced endoplasmic reticulum stress

ACS Fall 2020 Virtual Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.