2. Academic Validation
  3. Cancer-associated fibroblasts promote EGFR-TKI resistance via the CTHRC1/glycolysis/H3K18la positive feedback loop

Cancer-associated fibroblasts promote EGFR-TKI resistance via the CTHRC1/glycolysis/H3K18la positive feedback loop

  • Oncogene. 2025 Feb 26. doi: 10.1038/s41388-025-03318-y.
Chen Zhang # 1,  Wenxin Zhou # 1,  Hai Xu # 2,  Jiali Xu 1,  Jun Li 1,  Xinyin Liu 1,  Xiyi Lu 1,  Jiali Dai 1,  Yuqin Jiang 1,  Wei Wang 3,  Erbao Zhang 4 5,  Renhua Guo 6
Affiliations

Affiliations

  • 1 Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 2 Department of Radiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 3 Department of Thoracic Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. wwjsph@126.com.
  • 4 Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. erbaozhang@njmu.edu.cn.
  • 5 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China. erbaozhang@njmu.edu.cn.
  • 6 Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. rhguo@njmu.edu.cn.
  • # Contributed equally.
PMID: 40011576 DOI: 10.1038/s41388-025-03318-y
Abstract

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a major challenge in the treatment of lung Cancer. Cancer associated fibroblasts (CAFs) play a key role in promoting resistance to anti-cancer therapies. This study identified a subpopulation of CAFs characterized by the overexpression of collagen triple helix repeat-containing 1 (CTHRC1) through single-cell RNA Sequencing of lung Cancer patients undergoing EGFR-TKI treatment. These CTHRC1+ CAFs were enriched in drug-resistant tumors. Mechanistically, CTHRC1+ CAFs enhance the glycolytic activity of Cancer cells by activating the TGF-β/SMAD3 signaling pathway. Excess lactate produced in the process of glycolysis further upregulates CTHRC1 expression in CAFs through histone lactylation, creating a positive feedback loop that sustains EGFR-TKI resistance. The study also demonstrated that Gambogenic Acid, a natural compound, can disrupt this feedback loop, thereby improving the efficacy of EGFR-TKI therapy. Additionally, the presence of CTHRC1+ CAFs in tumor tissues could serve as a biomarker for predicting the response to EGFR-TKI therapy and patient prognosis. Overall, this study highlights the significant role of CAFs in EGFR-TKI resistance and suggests that targeting CTHRC1+ CAFs could be a promising strategy to overcome drug resistance in lung Cancer.

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