A fungal-derived benzothiazole derivative overcomes osimertinib resistance in NSCLC by targeting SCD1

Osimertinib resistance remains a critical factor for treatment failure in non-small cell lung cancer (NSCLC), making it of great clinical significance to develop novel agents that can overcome this resistance. Natural products are invaluable sources for anti-drug discovery. In this study, we first report that 6-(2-hydroxyethyl) benzo[d]thiazol-4-ol (HBT), a benzothiazole derivative isolated from the endophytic fungus Aspergillus sp. 1022LEF, effectively reverses osimertinib resistance both in vitro and in vivo. Our results demonstrate that HBT effectively inhibits the proliferation of osimertinib-resistant cells by inducing ferroptosis, a novel form of iron-dependent cell death driven by lipid peroxidation. This effect is partially dependent on stearoyl-CoA desaturase 1 (SCD1). Further mechanistic studies revealed that HBT acts as a novel SCD1 inhibitor by directly binding to SCD1 and promoting its degradation, thereby leading to lipid peroxidation and ferroptosis. In vivo experiments showed that HBT treatment significantly suppressed tumor growth in PC9-OR xenograft models, as evidenced by reduced tumor volume and weight. In summary, our study not only identifies HBT as a promising therapeutic candidate for overcoming osimertinib resistance in NSCLC but also suggest that SCD1 is a potential target for combating such resistance.