2024 Hot Topic in Basic & Translational Science: Tolerance & Resistance to Targeted Therapy in NSCLC - Posters-PP01.16: Ixazomib Overcomes Platinum Resistance and Induces Autophagy-Mediated Cell Death in Lung Adenocarcinoma

PP01.16: Ixazomib Overcomes Platinum Resistance and Induces Autophagy-Mediated Cell Death in Lung Adenocarcinoma

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The study investigates the potential of ixazomib (IXZ) as a treatment for lung adenocarcinoma (LUAD), particularly in overcoming resistance to platinum-based drugs like carboplatin (CBP). Lung cancer, especially LUAD, remains the leading cause of cancer-related deaths globally, often due to the development of resistance to standard treatments. Using an unbiased approach with connectivity mapping, the researchers identified ixazomib, an FDA-approved proteasome inhibitor used for multiple myeloma, as a promising candidate for LUAD treatment.<br /><br />The study tested ixazomib's efficacy on various human and mouse LUAD cell lines, showing that it significantly reduced cell viability, inhibited proliferation, and induced apoptosis. Ixazomib was notably effective against LUAD cells resistant to platinum-based chemotherapy. It worked synergistically with carboplatin to further reduce cell proliferation and migration, highlighting its potential as a chemosensitizer.<br /><br />Mechanistically, ixazomib was found to disrupt the integrinβ4/FAK/Src/β-catenin signaling pathway and induce the degradation of integrin β4 through a ubiquitin-mediated autophagy pathway. These actions not only inhibit cancer cell growth but also diminish cancer stem cell properties, offering a comprehensive approach to tackling LUAD resistance mechanisms.<br /><br />The results suggest that ixazomib, alone or in combination with carboplatin, could offer an innovative therapeutic strategy to improve treatment outcomes for LUAD, particularly in overcoming drug resistance. The study recommends further research to explore the mechanistic pathways in more detail and to potentially initiate clinical trials for more widespread application in LUAD treatment. The research was supported by funds from the Veteran Affairs and collaborations with the University of Nebraska Medical Center.

Asset Subtitle

Muthamil Iniyan Appadurai

Keywords

ixazomib

lung adenocarcinoma

drug resistance

carboplatin

proteasome inhibitor

integrinβ4/FAK/Src/β-catenin pathway

ubiquitin-mediated autophagy

cancer stem cells

chemotherapy

clinical trials