Targeting EGFR-Mcl-1 Axis by Piperlongumine as a Novel Strategy for Non-Small Cell Lung Cancer Therapy

Non-small cell lung cancer (NSCLC) is a malignancy that faces serious resistance challenges in treatment. In this study, we identified Piperlongumine as a promising therapeutic candidate to overcome Osimertinib resistance in NSCLC. We systematically investigated the inhibitory effect of Piperlongumine on NSCLC cells and confirmed that it could effectively inhibit the <i>in vitro</i> kinase activity of wild-type (WT), exon 19 deletion, and L858R/T790M-mutated EGFR. We also found that Piperlongumine-induced intrinsic apoptosis by interfering with the EGFR signaling pathway, which was characterized by the down-regulation of the anti-apoptotic protein Mcl-1. Further mechanistic studies revealed that Piperlongumine-induced degradation of Mcl-1 was dependent on the Akt-GSK3β signaling pathway. Additionally, Piperlongumine-promoted interaction between Mcl-1 and β-TRCP, thereby enhancing β-TRCP-mediated ubiquitination and the degradation of Mcl-1. Furthermore, Piperlongumine significantly inhibited tumor growth in both Osimertinib-sensitive and resistant NSCLC xenograft models. These findings highlight the potential of Piperlongumine as an effective agent in overcoming EGFR-targeted therapy resistance and suggest new avenues for its clinical application in NSCLC treatment.