Transfer of Damaged Mitochondria from Cancer Cells to Cancer-Associated Fibroblasts Promotes Tyrosine Kinase Inhibitor Tolerance in EGFR-Mutant Lung Cancer.

Abstract

Drug-tolerant persister (DTP) cells drive therapeutic resistance in EGFR-mutant lung adenocarcinoma. Using single-cell RNA sequencing, we identified a clinically significant RGS5+MYL9+ cancer-associated fibroblast (CAF) population that was associated with EGFR tyrosine kinase inhibitor (TKI) resistance and poor prognosis. These CAFs were recruited to DTP niches via CCL11 signaling, and they formed tunneling nanotubes through Miro1/RhoA activation induced by TKI-generated mitochondrial reactive oxygen species. Remarkably, RGS5+MYL9+ CAFs functioned as "metabolic sinks" by accepting tumor-derived damaged mitochondria, thereby promoting DTP survival. Treatment with fasudil, a Rho kinase inhibitor, effectively blocked mitochondrial transfer and restored sensitivity to the EGFR-TKI osimertinib in vivo. Together, this work reveals targetable stromal-tumor cross-talk that sustains DTP populations, proposing a combination therapy for overcoming EGFR-TKI resistance. Pharmacological blockade of nanotube-mediated mitochondrial transfer between tumor cells and RGS5+MYL9+ fibroblasts effectively overcome tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer, offering a clinically applicable strategy to enhance EGFR inhibitor efficacy.