2. Academic Validation
  3. circATF6 triggers calcium overload to synergize with EGFR-TKI in non-small cell lung cancer via modulation of proteostasis

circATF6 triggers calcium overload to synergize with EGFR-TKI in non-small cell lung cancer via modulation of proteostasis

  • Cell Rep. 2025 Dec 23;44(12):116659. doi: 10.1016/j.celrep.2025.116659.
Qianfan Hu 1,  Yajing Wang 2,  Yuxian Qian 1,  Zi Wang 1,  Hui Wang 1,  Frank Qingyun Wang 3,  Rutao Li 4,  Yipeng Feng 1,  Yijian Zhang 1,  Hanlin Ding 1,  Weiran Zhou 5,  Wei Zhang 6,  Qixing Mao 7,  Wenjie Xia 7,  Gaochao Dong 8,  Feng Jiang 9
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China; Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Nanjing 210009, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210009, China.
  • 2 Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Nanjing 210009, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210009, China; Department of Oncology, Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China.
  • 3 Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong 999077, China.
  • 4 Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215031, China.
  • 5 The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210009, China.
  • 6 Exchange, Development & Service Center for Science & Technology Talents, Beijing 100045, China.
  • 7 Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Nanjing 210009, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210009, China.
  • 8 Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Nanjing 210009, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210009, China. Electronic address: [email protected].
  • 9 Department of Thoracic Surgery, Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China; Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Nanjing 210009, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210009, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211116, China. Electronic address: [email protected].
PMID: 41351835 DOI: 10.1016/j.celrep.2025.116659
Abstract

Drug-tolerant persister (DTP) cells are a reversible, refractory population that contributes to tumor relapse during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy in non-small cell lung Cancer (NSCLC). Targeting the vulnerabilities of DTP cells constitutes an effective strategy to enhance the long-term efficacy of EGFR-TKIs. Here, we identify the circular RNA circATF6, which is specifically downregulated in DTP cells due to regulation by the splicing factor ADAR1. Restoration of circATF6 expression significantly enhances osimertinib (Osi) efficacy both in vitro and in vivo. Mechanistically, circATF6 interacts with the endoplasmic reticulum (ER) chaperone BiP/GRP78, inhibiting the activated adaptive unfolded protein response (UPR). This inhibition disrupts proteostasis, leading to ER fragmentation and CA2+ overload in the cytoplasm, ultimately triggering Apoptosis in DTP cells. Notably, lipid nanoparticle (LNP)-encapsulated circATF6 enhanced the antitumor effects of EGFR-TKI without significant toxicity. Our study provides a therapeutic strategy targeting circATF6 to synergize with EGFR-TKI in NSCLC.

Keywords

CP: cancer; CP: molecular biology; EGFR-TKI; ER chaperone; calcium; drug-tolerant persister; proteostasis; unfolded protein response.

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