Targeted degradation of estrogen receptor β to overcome Osimertinib resistance in non-small cell lung carcinoma.

Osimertinib resistance remains a major challenge in advanced non-small cell lung cancer (NSCLC) patients. Estrogen receptor β (ERβ) has been identified as a vital promoter in the emergence of Osimertinib resistance in NSCLC cells, however, the mechanism of action of ERβ underlining the development of acquired resistance to Osimertinib for NSCLC treatment remain unclear. To explore its therapeutic potential, we designed and synthesized a series of novel ERβ targeting PROteolysis Targeting Chimera (PROTAC) degraders for the first time to overcome Osimertinib resistance in NSCLC. Systematic SAR (Structure-activity relationship) study identified ERB-2 with excellent ERβ degradation activity and anti-tumor potency. Mechanistically, ERB-2-induced ERβ degradation regulates multiple cellular metabolic processes, cell cycle, and RNA translation. Noteworthily, ERB-2 could promote ROS accumulation, mitochondrial dysfunction, cell apoptosis and restore Osimertinib sensitivity in Osimertinib-resistant NSCLC cells, eventually lead to effective reversal of Osimertinib resistance in vivo. Collectively, this study identifies ERB-2 as a potent first-in-class ERβ degrader capable of overcoming Osimertinib resistance in NSCLC, putting forward potential solution for clinical unmet need in NSCLC treatment.