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

Area of Science:

• Oncology
• Cancer Biology
• Molecular Medicine

Background:

• Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a significant obstacle in lung cancer treatment.
• Cancer-associated fibroblasts (CAFs) are implicated in promoting therapeutic resistance.
• Identifying mechanisms of resistance is crucial for developing effective lung cancer therapies.

Purpose of the Study:

• To identify a specific subpopulation of CAFs involved in EGFR-TKI resistance.
• To elucidate the molecular mechanisms by which these CAFs confer resistance.
• To explore potential therapeutic strategies to overcome EGFR-TKI resistance.

Main Methods:

• Single-cell RNA sequencing of lung cancer patient tumors.
• Analysis of CAFs and their interaction with cancer cells.
• Investigation of the TGF-β/Smad3 signaling pathway and histone lactylation.
• In vivo and in vitro experiments evaluating Gambogenic Acid efficacy.

Main Results:

• A subpopulation of CAFs overexpressing collagen triple helix repeat-containing 1 (CTHRC1+ CAFs) was identified and found enriched in drug-resistant tumors.
• CTHRC1+ CAFs enhance cancer cell glycolysis via TGF-β/Smad3, leading to lactate production.
• Lactate upregulates CTHRC1 in CAFs through histone lactylation, creating a positive feedback loop sustaining resistance.
• Gambogenic Acid disrupted this feedback loop, enhancing EGFR-TKI efficacy.
• CTHRC1+ CAFs serve as a potential biomarker for predicting treatment response and prognosis.

Conclusions:

• CTHRC1+ CAFs play a critical role in mediating acquired resistance to EGFR-TKIs in lung cancer.
• Targeting CTHRC1+ CAFs represents a promising strategy to overcome therapeutic resistance.
• CTHRC1+ CAFs can be utilized as predictive biomarkers for EGFR-TKI therapy.