Ixazomib triggers autophagic degradation of MUC5AC/integrin-β4 and inhibits non-small cell lung cancer progression.

BACKGROUND: Lung cancer is the most common cause of cancer-related deaths. Despite recent advances in therapy, patients invariably develop resistance to standard treatments. Hence, there is an increasing need to identify newer treatment approaches to enhance the efficacy of currently used agents and improve outcomes. METHODS: An unbiased connectivity mapping analysis identified the proteasomal inhibitor ixazomib (IXZ), as a potentially effective agent against lung adenocarcinoma (LUAD). IXZ was studied for cell viability, cell cycle, migration, and apoptosis, alone or in combination with carboplatin (CBP), using human and mouse LUAD cell lines. The mechanisms were studied using a proteasome array, molecular approaches on proteasomal and autophagy pathway interventions, and in vivo lung orthotopic syngeneic mouse models. RESULTS: We identified IXZ as a potential agent that inhibits LUAD cell growth, G2/M arrest, and promotes cell death, both as a single agent and in combination with CBP. IXZ induced DNA damage and attenuated repair mechanisms in cisplatin-resistant cells, suggesting a potential therapeutic role in overcoming platinum resistance. Using the mCherry-GFP-LC3B reporter assay and pathway interventions (silencing ATG5, UBE2N, and BAG3 genes, and autophagy inhibitors 3-MA and HCQ), we found that IXZ degraded MUC5AC/integrin-β4 via the ubiquitin-mediated autophagy pathway. We also showed that IXZ destabilizes MUC5AC by blocking interaction with the deubiquitinase UCHL1. In vivo treatment studies further demonstrated that IXZ significantly decreased tumor burden by blocking the MUC5AC/UCHL1 oncogenic axis. CONCLUSIONS: IXZ effectively inhibited LUAD tumor growth and may overcome platinum resistance. These findings warrant further investigation into the clinical role of IXZ alone or in combination with CBP or other chemotherapies in patients with LUAD.