5-HT regulates resistance to aumolertinib by attenuating ferroptosis in lung adenocarcinoma

Abstract Resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) remains a critical clinical challenge in EGFR mutant lung adenocarcinoma (LUAD). Therefore, it is urgent to explore personalized treatment strategies based on distinct resistance mechanisms to reverse EGFR-TKI resistance. Herein, we found that HER2 S310F mutation contributes to third-generation EGFR-TKI resistance, driven by the accumulation of neurotransmitter 5-hydroxytryptamine (5-HT). Mechanistically, 5-HT interacted with 5-HT3 receptor, triggering calcium ion (Ca 2+ ) influx and subsequent activation of the Ca 2+ /CAMKK2/AMPK pathway. This pathway activation conferred ferroptosis resistance, thereby driving aumolertinib resistance. 5-HT3 receptor (HTR3) antagonists were pinpointed as potential agents for reversing aumolertinib resistance through drug library screening and transcriptomics analysis. We demonstrated that pharmacologically targeting 5-HT/HTR3 signaling with the clinically approved HTR3 antagonist palonosetron effectively restores aumolertinib sensitivity. Importantly, we showed that elevated 5-HT levels in patient plasma play a potential role in predicting EGFR-TKI resistance. Our data highlight the critical role of 5-HT and ferroptosis in the development of aumolertinib resistance, and propose HTR3 antagonists as a novel combination therapy strategy for LUAD treatment with aumolertinib.