2. Academic Validation
  3. Hypoxia-inducible APCDD1L-AS1 promotes osimertinib resistance by stabilising DLST to drive tricarboxylic acid cycle in lung adenocarcinoma

Hypoxia-inducible APCDD1L-AS1 promotes osimertinib resistance by stabilising DLST to drive tricarboxylic acid cycle in lung adenocarcinoma

  • J Exp Clin Cancer Res. 2025 Jul 9;44(1):197. doi: 10.1186/s13046-025-03462-z.
Quanli Zhang # 1,  Ye Shen # 2,  Yuru Che # 3,  Lili Jia # 3,  Xiang Xiao # 3,  Hao Xu 3,  Chi Su 3,  Kemin Sun 3,  Limin Zheng 3,  Jiawen Xu 3,  Jingwen Hu 4,  Chaofeng Zhang 5,  Dihan Zhu 6,  Ming Li 7
Affiliations

Affiliations

  • 1 School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 210009, Jiangsu, P. R. China.
  • 2 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 210009, Jiangsu, P. R. China.
  • 3 Department of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210009, Jiangsu, P. R. China.
  • 4 Department of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210009, Jiangsu, P. R. China. h136271114@163.com.
  • 5 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 210009, Jiangsu, P. R. China. zhangchaofeng@cpu.edu.cn.
  • 6 School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 210009, Jiangsu, P. R. China. zdhjing@live.com.
  • 7 Department of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210009, Jiangsu, P. R. China. mingli@njmu.edu.cn.
  • # Contributed equally.
PMID: 40634956 DOI: 10.1186/s13046-025-03462-z
Abstract

Acquired resistance is unavoidable in lung adenocarcinoma (LUAD) treated with osimertinib, however, the underlying mechanisms remain largely unknown. Here, we report that the long non-coding RNA (lncRNA) APCDD1L-AS1 is upregulated in osimertinib-resistant LUAD tissues and cells and is associated with short survival of osimertinib-resistant LUAD patients. Our data showed that APCDD1L-AS1 upregulation is an independent risk factor for overall survival in patients with osimertinib-resistant LUAD. APCDD1L-AS1 knockdown enhanced osimertinib sensitivity both in vitro and in vivo, whereas APCDD1L-AS1 overexpression promoted osimertinib resistance. Mechanistically, APCDD1L-AS1 accelerates the tricarboxylic acid (TCA) cycle by forming complexes and maintaining the stability of dihydrolipoamide S-succinyltransferase (DLST), which inhibits the ubiquitination and degradation of DLST. Moreover, we demonstrate that hypoxia-inducible factor (HIF)-1α transcriptionally activates APCDD1L-AS1 by binding to the APCDD1L-AS1 promoter region under hypoxic conditions. Overall, our data confirm that APCDD1L-AS1 is upregulated by hypoxia-induced HIF-1α, which drives the TCA cycle by stabilising DLST to further promote osimertinib resistance in LUAD. Our findings provide new insights into the role of HIF-1α/APCDD1L-AS1/DLST axis-related reprogramming of hypoxia and the TCA balance in conferring osimertinib resistance in LUAD and confirm the therapeutic potential for targeting the APCDD1L-AS1.

Keywords

Hypoxia; Long non-coding RNAs; Lung adenocarcinoma; Osimertinib-resistant; Tricarboxylic acid cycle.

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