Abstract 1745: Exploiting vulnerabilities to nanoparticle induced lipid peroxidation and proteotoxicity to treat drug resistant lung cancer

Abstract

Abstract Protein quality control plays an essential role in cell survival. Clinically translated strategies to target protein quality control in cancer show some efficacy, but off-target effects are severe. We are investigating a new approach using nanomaterials to induce lipid peroxidation to trigger a cascade of protein oxidation, protein misfolding, and decreased protein degradative capacity in cancer cells without affecting normal cells. Our studies show that silver nanoparticles (AgNPs) cause dramatic increases in lipid peroxidation, 4-hydroxynonenal adducts (4-HNE), protein oxidation, protein aggregation, and proteotoxic stress signaling in a mesenchymal-like subset of non-small cell lung (NSCLC) and other cancers at doses that do not affect normal cells in vitro or vivo. Notably, AgNP sensitive NSCLCs are inherently resistant to clinically relevant therapies including epidermal growth factor receptor tyrosine kinase inhibitors ((EGFR-TKIs) e.g. erlotinib, gefitinib, olfatinib) and cisplatin. We identified two defining characteristics causing some cancers to be sensitive to AgNPs. The first is enrichment of cell membranes in polyunsaturated fatty acids (PUFAs), especially arachidonic (AA) and adrenic acid (AdA), which are prone to oxidation. The second is high-level synthesis and secretion of extracellular matrix (ECM), especially fibronectin and collagen, which places AgNP sensitive cancers under substantial baseline endoplasmic reticulum stress, making them susceptible to agents that increase proteotoxicity. Mechanistically, we find that in PUFA-enriched cancers, signaling from ECM sustains the AgNP sensitive phenotype by stimulating Akt activity and stabilizing cytoplasmic β-catenin. Transcriptionally active β-catenin increases expression of fibronectin and collagen, resulting in a positive feedback loop locking cells into the AgNP sensitive phenotype. Use of AgNPs to targeting vulnerabilities associated with ECM synthesis and signaling downstream of β-catenin is a novel approach to overcoming multiple EGFR-TKI resistance mechanisms. Ultimately, our goal is to elucidate the precise mechanism by which AgNPs overcome resistance to clinically available EGFR-TKIs. Identification of the specific drivers of sensitivity to AgNPs (and potentially other metal nanoparticles) will guide development of therapeutic metal nanoparticles, enable selection of cancer patients who will benefit most or are at greatest risk to nanomaterial exposure, and will spur innovation of other treatments that exploit the vulnerabilities we identify. Citation Format: Christina Snyder, Monica Rohde, Ravi N. Singh. Exploiting vulnerabilities to nanoparticle induced lipid peroxidation and proteotoxicity to treat drug resistant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1745.