2. Academic Validation
  3. PrPC controls epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient follow-up

PrPC controls epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient follow-up

  • Oncogene. 2024 Aug 15. doi: 10.1038/s41388-024-03130-0.
Claire Lailler 1,  Audrey Didelot # 1,  Simon Garinet # 1,  Hugo Berthou 1,  Marine Sroussi 1 2,  Aurélien de Reyniès 1,  Shoukat Dedhar 3,  Séverine Martin-Lannerée 1,  Elizabeth Fabre 4,  Françoise Le Pimpec-Barthes 5,  Alexandre Perrier 1,  Virginie Poindessous 1,  Audrey Mansuet-Lupo 6,  Fatima Djouadi 1,  Jean-Marie Launay 7 8,  Pierre Laurent-Puig 1 2,  Hélène Blons # 9 10,  Sophie Mouillet-Richard # 11
Affiliations

Affiliations

  • 1 Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France.
  • 2 Institut du Cancer Paris CARPEM, AP-HP, Department of Genetics and Molecular Medicine, Hôpital Européen Georges Pompidou, Paris, France.
  • 3 Genetics Unit, Integrative Oncology, BC Cancer, Vancouver, BC, Canada.
  • 4 AP-HP Department of Thoracic Oncology, Hôpital Européen Georges Pompidou, Paris, France.
  • 5 AP-HP Department of Thoracic Surgery, Hôpital Européen Georges Pompidou, Paris, France.
  • 6 AP-HP Department of Pathology, Hôpital Cochin, Université Paris Cité, Paris, France.
  • 7 INSERM U942 Lariboisière Hospital, Paris, France.
  • 8 Pharma Research Department, F. Hoffmann-La-Roche Ltd., Basel, Switzerland.
  • 9 Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France. helene.blons@aphp.fr.
  • 10 Institut du Cancer Paris CARPEM, AP-HP, Department of Biochemistry, Pharmacogenetics and Molecular Oncology, Hôpital Européen Georges Pompidou, Paris, France. helene.blons@aphp.fr.
  • 11 Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France. sophie.mouillet-richard@parisdescartes.fr.
  • # Contributed equally.
PMID: 39147880 DOI: 10.1038/s41388-024-03130-0
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15772
    99.96%, Mutant-Selective EGFR Inhibitor