2. Academic Validation
  3. 5-HT regulates resistance to aumolertinib by attenuating ferroptosis in lung adenocarcinoma

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

  • EMBO Mol Med. 2025 Oct;17(10):2586-2611. doi: 10.1038/s44321-025-00293-5.
Yuanying Feng # 1 2 3 4,  Yuchao He # 1 3,  Ran Zuo # 3 5,  Wenchen Gong 3 6,  Yuan Gao 1 2 3,  Yun Wang 1 2 3,  Yu Wang 1 3,  Wenshuai Chen 1 3,  Liwei Chen 1 3,  Yi Luo 1 3,  Dongqi Yuan 1 2 3,  Peng Chen 7 8,  Hua Guo 9 10
Affiliations

Affiliations

  • 1 Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
  • 2 Department of Thoracic Oncology, Lung Cancer Diagnosis and Treatment Center, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
  • 3 National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China.
  • 4 Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 101149, Beijing, China.
  • 5 Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
  • 6 Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
  • 7 Department of Thoracic Oncology, Lung Cancer Diagnosis and Treatment Center, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China. chenpeng@tjmuch.com.
  • 8 National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China. chenpeng@tjmuch.com.
  • 9 Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China. guohua@tjmuch.com.
  • 10 National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China. guohua@tjmuch.com.
  • # Contributed equally.
PMID: 40897859 DOI: 10.1038/s44321-025-00293-5
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 (CA2+) influx and subsequent activation of the CA2+/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.

Keywords

5-Hydroxytryptamine; Aumolertinib; EGFR-TKI Resistance; Ferroptosis; HTR3 Antagonists.

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