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

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.