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

Autor: Lailler C; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France., Didelot A; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France., Garinet S; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France., Berthou H; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France., Sroussi M; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France.; Institut du Cancer Paris CARPEM, AP-HP, Department of Genetics and Molecular Medicine, Hôpital Européen Georges Pompidou, Paris, France., de Reyniès A; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France., Dedhar S; Genetics Unit, Integrative Oncology, BC Cancer, Vancouver, BC, Canada., Martin-Lannerée S; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France., Fabre E; AP-HP Department of Thoracic Oncology, Hôpital Européen Georges Pompidou, Paris, France., Le Pimpec-Barthes F; AP-HP Department of Thoracic Surgery, Hôpital Européen Georges Pompidou, Paris, France., Perrier A; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France., Poindessous V; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France., Mansuet-Lupo A; AP-HP Department of Pathology, Hôpital Cochin, Université Paris Cité, Paris, France., Djouadi F; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France., Launay JM; INSERM U942 Lariboisière Hospital, Paris, France.; Pharma Research Department, F. Hoffmann-La-Roche Ltd., Basel, Switzerland., Laurent-Puig P; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France.; Institut du Cancer Paris CARPEM, AP-HP, Department of Genetics and Molecular Medicine, Hôpital Européen Georges Pompidou, Paris, France., Blons H; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France. helene.blons@aphp.fr.; Institut du Cancer Paris CARPEM, AP-HP, Department of Biochemistry, Pharmacogenetics and Molecular Oncology, Hôpital Européen Georges Pompidou, Paris, France. helene.blons@aphp.fr., Mouillet-Richard S; Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France. sophie.mouillet-richard@parisdescartes.fr.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 Sep; Vol. 43 (37), pp. 2781-2794. Date of Electronic Publication: 2024 Aug 15.
DOI: 10.1038/s41388-024-03130-0
Abstrakt: 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 PrP C 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 PrP C is associated with EMT. By manipulating the levels of PrP C in different EGFR-mutated NSCLC cell lines, we firmly establish that the expression of PrP C is mandatory for cells to maintain or acquire a mesenchymal phenotype. Mechanistically, we show that PrP C operates through an ILK-RBPJ cascade, which also controls the expression of EGFR. Our data further demonstrate that PrP C 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 PrP C 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 PrP C as a candidate driver of EMT-dependent resistance to EGFR-TKI in NSCLC. They further suggest that monitoring plasma PrP C levels may represent a valuable non-invasive strategy for patient follow-up and warrant considering PrP C -targeted therapies for EGFR-mutated NSCLC patients with TKI failure.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: