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PrPC controls epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient
Claire Lailler1, Audrey Didelot1, Simon Garinet1
1Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France.
Abstract:
Patients with EGFR-mutated non-small cell lung cancer (NSCLC) benefit from treatment with tyrosine kinase inhibitors (TKI) targeting EGFR. Despite improvements in patient care, especially with the 3rd generation TKI osimertinib, disease relapse is observed in all patients. Among the various processes involved in TKI resistance, epithelial-to-mesenchymal transition (EMT) is far from being fully characterized. We hypothesized that the cellular prion protein PrPC could be involved in EMT and EGFR-TKI resistance in NSCLC. Using 5 independent lung adenocarcinoma datasets, including our own cohort, we document that the expression of the PRNP gene encoding PrPC is associated with EMT. By manipulating the levels of PrPC in different EGFR-mutated NSCLC cell lines, we firmly establish that the expression of PrPC is mandatory for cells to maintain or acquire a mesenchymal phenotype. Mechanistically, we show that PrPC operates through an ILK-RBPJ cascade, which also controls the expression of EGFR. Our data further demonstrate that PrPC levels are elevated in EGFR-mutated versus wild-type tumours or upon EGFR activation in vitro. In addition, we provide evidence that PRNP levels increase with TKI resistance and that reducing PRNP expression sensitizes cells to osimertinib. Finally, we found that plasma PrPC levels are increased in EGFR-mutated NSCLC patients from 2 independent cohorts and that their longitudinal evolution mirrors that of disease. Altogether, these findings define PrPC as a candidate driver of EMT-dependent resistance to EGFR-TKI in NSCLC. They further suggest that monitoring plasma PrPC levels may represent a valuable non-invasive strategy for patient follow-up and warrant considering PrPC-targeted therapies for EGFR-mutated NSCLC patients with TKI failure.
Insights
Cellular prion protein PrPC drives resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer by promoting epithelial-to-mesenchymal transition. Monitoring plasma PrPC may aid patient follow-up and guide targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- EGFR-mutated non-small cell lung cancer (NSCLC) patients benefit from EGFR tyrosine kinase inhibitors (TKIs).
- Disease relapse and resistance to TKIs, including osimertinib, remain significant challenges in NSCLC treatment.
- Epithelial-to-mesenchymal transition (EMT) is implicated in TKI resistance but its underlying mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of cellular prion protein (PrPC) in EMT and EGFR-TKI resistance in NSCLC.
- To elucidate the molecular mechanisms by which PrPC influences EMT and TKI sensitivity.
- To assess the potential of PrPC as a biomarker for patient monitoring and a therapeutic target.
Main Methods:
- Analysis of 5 independent lung adenocarcinoma datasets to correlate PRNP gene expression with EMT.
- Manipulation of PrPC levels in EGFR-mutated NSCLC cell lines to assess its impact on mesenchymal phenotype.
- Mechanistic studies involving ILK-RBPJ signaling cascade and EGFR expression.
- Measurement of plasma PrPC levels in independent patient cohorts.
Main Results:
- PRNP gene expression is associated with EMT in NSCLC.
- PrPC expression is essential for maintaining or acquiring a mesenchymal phenotype in NSCLC cells.
- PrPC regulates EMT via an ILK-RBPJ cascade that also controls EGFR expression.
- Elevated PrPC levels are observed in EGFR-mutated tumors and upon EGFR activation.
- PRNP levels increase with TKI resistance, and reducing PRNP sensitizes cells to osimertinib.
- Plasma PrPC levels are elevated in EGFR-mutated NSCLC patients and correlate with disease status.
Conclusions:
- PrPC is identified as a key driver of EMT-dependent resistance to EGFR-TKIs in NSCLC.
- PrPC represents a potential therapeutic target for overcoming TKI resistance in NSCLC.
- Plasma PrPC monitoring offers a promising non-invasive strategy for tracking disease progression and treatment response in NSCLC patients.
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