Piperlongumine overcomes osimertinib resistance via governing ubiquitination-modulated Sp1 turnover

• DOI: 10.1172/jci.insight.186165
• Publication Date: 2025-03-23T18:00:31Z
• Authors: Ruirui Wang; Qiang Wang; Jinzhuang Liao; Xinfang Yu; Wei Li
• Keywords: Osimertinib

Non-small cell lung cancer (NSCLC) is a common cause of cancer-related deaths worldwide, and its incidence has been increasing in recent years. While targeted therapies like osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor, have brought about notable improvements patient outcomes for advanced NSCLC, the challenge acquired drug resistance persists. Here, we found that cellular mesenchymal-epithelial transition (c-Met) was highly expressed osimertinib-resistant cells, depletion c-Met markedly inhibited cells ex vivo vivo, suggesting potential target to address osimertinib resistance. Through screening process using natural product compound library, identified piperlongumine as potent inhibitor overcome Furthermore, combined treatment exhibited robust antitumor effects resistant partially restoring their sensitivity osimertinib. Additionally, discovered could enhance interaction between E3 ligase RNF4 Sp1, inhibit phosphorylation Sp1 at Thr739, facilitate ubiquitination degradation lead destabilization, trigger intrinsic apoptosis cells. In summary, our study sheds light on overcoming resistance, offering new strategies perspectives clinical management drug-resistant NSCLC.