Lycorine Exerts Antitumor Effects on the Osimertinib‐Resistant Non‐Small Cell Lung Cancer by Inhibiting NOTCH3/HES1 Signaling

The resistance of non-small cell lung cancer (NSCLC) to osimertinib unavoidably occurs in clinical use. Lycorine is isolated from Amaryllidaceae genera and possesses a variety of pharmacological effects including anticancer. Here, we investigated the influences of lycorine on osimertinib-resistant cells and its underlying mechanisms. The data from CCK8 assay, wound healing, and migration assay revealed the inhibitory effect of lycorine in the NSCLC cells resistant to osimertinib. In vivo, lycorine reduced the growth of osimertinib-resistant NSCLC xenografts. The results from transcriptomic analysis showed that lycorine significantly decreased the level of Notch3 mRNA in osimertinib-resistant PC9 (PC9/OR) cells. It was verified that lycorine indeed lowered the level of Notch3 mRNA/protein and its downstream Hes1 protein in osimertinib-resistant cells. The MMP9 and MMP2 protein levels were also lessened in the resistant cells after lycorine treatment. Moreover, Notch3/Hes1 protein levels were higher in osimertinib-resistant cells than those in osimertinib-sensitive cells. Notch3 and Hes1 knockdown promoted the antiproliferation and anti-migration effects of osimertinib in the resistant cells. Notably, lycorine enhanced the antitumor activity of osimertinib against its resistant cells both in vitro and in vivo. Overall, our data reveal that lycorine inhibits the proliferation and metastasis of osimertinib-resistant NSCLC cells via Notch3/Hes1 pathway.