Lysine methylation-mediated SMYD2 degradation by casticin sensitizes non-small-cell lung cancer cells to osimertinib therapy.

The application of tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) significantly improves the treatment of non-small-cell lung cancer (NSCLC). However, primary and acquired resistance limit the efficacy of EGFR-TKIs, which remain to be clarified. In this study, we found that Casticin effectively inhibited both EGFR-mutant and RAS-mutant lung cancer cells and sensitized cells to EGFR-TKIs by targeting SMYD2 in vitro and in vivo. Mechanistically, Casticin bound to SMYD2, inhibited SMYD2 activity, and promoted SMYD2 K80 methylation by reducing the interaction of SMYD2 and KDM5B, which subsequently augmented SMYD2 degradation via STUB1-mediated ubiquitination. SMYD2 and KDM5B overexpression counteracted the cytotoxic effects of Casticin. Knockdown or inhibition of SMYD2 increased cell sensitivity to EGFR-TKIs in vitro and in vivo. Collectively, these results indicated that Casticin suppresses and sensitizes non-small-cell lung cancer cells to EGFR-TKIs. Casticin may serve as a sensitizing agent by targeting SMYD2 to improve the efficacy of EGFR-TKIs.