USP8 is a novel target for overcoming gefitinib resistance in lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Non-small cell lung cancer (NSCLC) treatment often involves EGF receptor-tyrosine kinase inhibitors (EGFR-TKIs).
• Acquired resistance to EGFR-TKIs is a major clinical challenge, frequently driven by secondary EGFR mutations or MET gene amplification.
• Identifying novel therapeutic targets is crucial for overcoming resistance in NSCLC.

Purpose of the Study:

• To investigate ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target in both gefitinib-resistant and gefitinib-sensitive NSCLC.
• To evaluate the selective efficacy of targeting USP8 in NSCLC cells compared to normal cells.

Main Methods:

• Assessing the impact of USP8 knockdown on NSCLC cell viability in vitro.
• Evaluating the effects of a synthetic USP8 inhibitor on NSCLC cells and normal cells in cell culture.
• Testing the efficacy of USP8 inhibition in a xenograft mouse model of NSCLC.

Main Results:

• USP8 knockdown selectively eliminated gefitinib-resistant NSCLC cells with minimal toxicity to normal cells.
• Genetic silencing of USP8 resulted in decreased expression of key receptor tyrosine kinases (RTKs), including EGFR and MET.
• A synthetic USP8 inhibitor significantly reduced the viability of both gefitinib-resistant and -sensitive NSCLC cells by downregulating RTKs.
• In vivo studies demonstrated significant tumor size reduction in mice treated with a USP8 inhibitor.

Conclusions:

• USP8 inhibition or reduced expression selectively targets and kills NSCLC cells, including resistant phenotypes.
• USP8 represents a promising novel therapeutic target for both gefitinib-sensitive and gefitinib-resistant NSCLC.