2. Academic Validation
  3. Hypoxia-induced exosomal LUCAT1 promotes osimertinib resistance in lung adenocarcinoma by stabilizing c-MET

Hypoxia-induced exosomal LUCAT1 promotes osimertinib resistance in lung adenocarcinoma by stabilizing c-MET

  • Cell Death Dis. 2025 Oct 27;16(1):763. doi: 10.1038/s41419-025-08100-2.
Jianting Du # 1 2 3,  Bin Zheng # 1 2 3,  Jiekun Qian # 1 2 3,  Guanglei Huang 1 2 3,  Wenjie Yuan 1 2 3,  Renjie Huang 1 2 3,  Xian Gong 1 2 3,  Guobing Xu 1 2 3,  Bixing Zhao 4,  Xiaolong Liu 4,  Yingchao Wang 5,  Zhang Yang 6 7 8,  Chun Chen 9 10 11
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
  • 2 Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, Fuzhou, Fujian, China.
  • 3 Clinical Research Center for Thoracic Tumors of Fujian Province, Fuzhou, Fujian, China.
  • 4 The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China.
  • 5 The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China. yingchaowang@live.com.
  • 6 Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China. fjxh_zhang2021@163.com.
  • 7 Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, Fuzhou, Fujian, China. fjxh_zhang2021@163.com.
  • 8 Clinical Research Center for Thoracic Tumors of Fujian Province, Fuzhou, Fujian, China. fjxh_zhang2021@163.com.
  • 9 Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China. chenchun0209@fjmu.edu.cn.
  • 10 Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, Fuzhou, Fujian, China. chenchun0209@fjmu.edu.cn.
  • 11 Clinical Research Center for Thoracic Tumors of Fujian Province, Fuzhou, Fujian, China. chenchun0209@fjmu.edu.cn.
  • # Contributed equally.
PMID: 41145422 DOI: 10.1038/s41419-025-08100-2
Abstract

Osimertinib resistance poses a major challenge in treating advanced EGFR-mutant lung adenocarcinoma (LUAD). Exosomes, key mediators of intercellular communication, may contribute to drug resistance, but their specific role in osimertinib resistance remains unclear. This study aimed to elucidate the function and mechanisms of hypoxia-induced exosomes (HExo) in promoting osimertinib resistance in LUAD, with the goal of identifying potential diagnostic biomarkers and therapeutic targets. Cell survival under osimertinib treatment was analyzed using CCK8 and colony formation assays, while exosomal LUCAT1 was identified via RNA-seq and validated by qRT-PCR. Biological roles of LUCAT1 were assessed through in vitro and in vivo experiments, including immunoblotting, RNA immunoprecipitation (RIP)-qPCR, xenograft tumor models, and Organoid models. Results demonstrated that hypoxia-induced exosomal LUCAT1 reduced the sensitivity of recipient LUAD cells to osimertinib. Mechanistically, LUCAT1 promoted osimertinib resistance by preventing c-MET degradation and activating downstream Akt/mTOR and ERK pathways. Targeting c-MET effectively restored osimertinib sensitivity in resistant cells. Moreover, higher levels of exosomal LUCAT1 were significantly associated with poor therapeutic responses to osimertinib in patients. In conclusion, hypoxia-induced exosomal LUCAT1 drives osimertinib resistance by stabilizing c-MET and activating its downstream pathways. Plasma exosomal LUCAT1 levels are closely linked to osimertinib resistance and may serve as an ideal liquid biopsy target for monitoring patient response.

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