Patients diagnosed with EGFR-mutated non-small cell lung cancer (NSCLC) experience therapeutic advantages from EGFR-targeted tyrosine kinase inhibitors (TKIs). Even though third-generation agents like osimertinib have enhanced clinical outcomes, every patient eventually encounters tumor progression. Of the diverse pathways leading to TKI resistance, the role of epithelial-to-mesenchymal transition (EMT) is still not comprehensively defined. We postulated that the cellular prion protein, denoted PrPC, may contribute to EMT and resistance against EGFR-TKIs in NSCLC. Analyzing 5 separate lung adenocarcinoma datasets—one of which is our own collection—we confirm a correlation between PRNP gene expression (which codes for PrPC) and EMT signatures. Through alteration of PrPC amounts in multiple EGFR-mutated NSCLC cell models, we robustly demonstrate that PrPC is required for sustaining or developing mesenchymal characteristics. On a mechanistic basis, PrPC exerts its effects via an ILK-RBPJ pathway that simultaneously modulates EGFR levels. Additionally, our findings reveal higher PrPC abundance in EGFR-mutated tumors relative to wild-type counterparts, as well as increased expression upon EGFR stimulation in cell culture. We further establish that PRNP transcription escalates alongside acquired TKI resistance, while downregulation of PRNP renders cells more responsive to osimertinib. Moreover, in 2 distinct patient cohorts with EGFR-mutated NSCLC, circulating plasma PrPC concentrations were found to be elevated, and their changes over time paralleled disease trajectory. Taken together, these observations identify PrPC as a plausible facilitator of EMT-associated resistance to EGFR-TKIs in NSCLC. The results also imply that serial measurement of plasma PrPC could offer a practical, minimally invasive method for monitoring patients and justify evaluating therapies aimed at PrPC in EGFR-mutated NSCLC cases refractory to TKIs.
