Epidermal growth factor receptor (EGFR) activation contributes to pancreatic cancer etiology, yet anti-EGFR therapy offers minimal clinical benefits in patients with KRAS mutations. We report that plasminogen activator inhibitor-1 (PAI-1) derived from cancer-associated fibroblasts (CAFs) is selectively elevated in KRAS-mutant tumors and functions as a ligand of EGFR, contributing to resistance to anti-EGFR therapy. Ablation of stromal PAI-1 breaks the CAF-tumor interaction, curbing tumor growth and enhancing the therapeutic efficacy of anti-EGFR therapy in both genetically engineered mouse models and patient-derived xenografts. Mechanistically, KRAS mutation in PDAC activates c-Myc to release IL-1α from PDAC cells to stimulate NF-κB signaling in CAFs to turn on the transcription of PAI-1. PDAC patients with KRAS mutations have higher plasma PAI-1 levels than those with wild-type KRAS. Our findings reveal a mechanism through which CAFs and tumor cells are regulated by the interaction between PAI-1 secreted by CAFs and EGFR on tumor cells. Importantly, the newly identified ligand-receptor interaction of PAI-1-EGFR in the tumor microenvironment of pancreatic cancer may open a new avenue for understanding receptor biology. Epidermal growth factor receptor (EGFR) signaling contributes to pancreatic cancer progression, but therapies are often ineffective in tumors with KRAS mutations. Here, the authors show that cancer-associated fibroblast–derived PAI-1 acts as an EGFR ligand in KRAS-mutant pancreatic cancer, promoting tumor growth and resistance to anti-EGFR therapy.
Wang et al. (Sat,) studied this question.