WCLC 2025 - Posters & ePosters-P3.12.60 The Combination of USP24-i-101-Astemizole Sensitizes the Cytotoxicity of Taxol and Gefitinib in Drug-Resistant Lung Cancer

P3.12.60 The Combination of USP24-i-101-Astemizole Sensitizes the Cytotoxicity of Taxol and Gefitinib in Drug-Resistant Lung Cancer

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This study investigates overcoming drug resistance in lung cancer by targeting the deubiquitinating enzyme USP24, implicated in cancer drug resistance mechanisms. Researchers utilized the Connectivity Map (CMap) approach to generate a gene signature of USP24 activity and identify existing drugs that counteract this signature, aiming to repurpose them to sensitize resistant lung cancer cells to chemotherapy and targeted therapy.<br /><br />Several candidate drugs emerged from screening that have not yet been used in lung cancer clinical trials, including astemizole, a known antihistamine. Functional enrichment analysis revealed numerous USP24-interacting proteins involved in cancer-related pathways. Experimental results demonstrated that combining a novel USP24 inhibitor (USP24-i-101) with astemizole synergistically enhanced the cytotoxicity of Taxol (a chemotherapy agent) and Gefitinib (an EGFR-targeted therapy) in drug-resistant lung cancer cell lines, including A549 and HCC827.<br /><br />Combination index (CI) analysis indicated strong synergism (CI < 1) between USP24-i-101 and astemizole when combined with Gefitinib or Taxol, effectively reducing viability of resistant cancer cells. By inhibiting USP24 activity, this drug combination overcomes resistance mechanisms, enhancing anti-cancer efficacy. Other studied repurposed drugs (like dexamethasone) showed antagonistic or additive rather than synergistic effects.<br /><br />Overall, the findings demonstrate that targeting USP24 with specific inhibitors plus utilizing repurposed drugs such as astemizole can sensitize resistant lung cancer cells to both chemotherapy and molecular targeted therapy. This combinatorial approach holds promise for improving treatment responses in lung cancer patients with drug resistance, providing a novel strategy for overcoming otherwise refractory disease. The study highlights the value of gene signature-driven drug repurposing to identify therapeutics that modulate resistance-associated targets like USP24.

Asset Subtitle

Jan-Jong Hung

Meta Tag

Speaker Jan-Jong Hung

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

USP24

lung cancer

drug resistance

Connectivity Map

gene signature

drug repurposing

astemizole

USP24 inhibitor

Taxol

Gefitinib