| Title: |
Profiling of Extracellular Vesicles of Non-Small Cell Lung Cancer Reveals Proteins Associated With Osimertinib Resistance |
| Authors: |
Cáceres-Verschae, Albano; Hååg, Petra; Joelsson, Sofia; Hydbring, Per; Franzén, Bo; Végvári, Ákos; Eide, Inger Johanne Z.; Agarwal, Nupur; Sahu, Siddharth Sourabh; Stridfeldt, Fredrik; De Petris, Luigi; Dev, Apurba; Ekman, Simon; Brustugun, Odd Terje; Lewensohn, Rolf; Viktorsson, Kristina |
| Publisher Information: |
Uppsala universitet, Fasta tillståndets elektronik; Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.; Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.; Vestre Viken Hosp Trust, Sect Oncol, Drammen, Norway.;Univ Oslo, Dept Clin Med, Dept Canc Genet,Inst Canc Res, Norwegian Radium Hosp,Oslo Univ Hosp, Oslo, Norway.; KTH Royal Inst Technol, Sch Engn Sci, Dept Appl Phys, Stockholm, Sweden.; Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Theme Canc Patient Area Head Neck Lung & Skin Canc, Stockholm, Sweden. |
| Publication Year: |
2026 |
| Collection: |
Uppsala University: Publications (DiVA) |
| Subject Terms: |
biomarkers; extracellular vesicles; mutant epidermal growth factor receptor; non-small cell lung cancer; osimertinib; Cancer and Oncology; Cancer och onkologi; Cell and Molecular Biology; Cell- och molekylärbiologi; Neurosciences; Neurovetenskaper |
| Description: |
Precision cancer medicine with small tyrosine kinase inhibitors (TKIs) directed toward oncogenic drivers, are important treatment regimens for solid tumours. The epidermal growth factor receptor (EGFR)-TKI osimertinib is a preferred therapy for patients with non-small cell lung cancer (NSCLC) driven by activating mutations in EGFR, unfortunately responses are heterogeneous. This calls for non-invasive methods to predict or monitor treatment response, for example, via biomarker analyses in blood. To reveal such putative biomarkers, we analysed the proteome of extracellular vesicles (EVs) from osimertinib resistant or responsive NSCLC cells in vitro and from EVs isolated from serum samples of NSCLC patients treated with osimertinib in second line within the phase II clinical trial TREM. The protein cargo of the EVs was analysed by mass spectrometry (MS) and proximity extension assay (PEA). Western blotting, ELISA and single vesicle analysis was performed to validate and further confirm the expression of certain proteins. MS profiling of the NSCLC cells and their released EVs revealed a protein signature associated with osimertinib refractoriness. Among them were CSPG4, HSPG2, MCAM, L1CAM, TAGLN, THBS1 and TNC. GO-pathway analysis related several of these proteins to the focal adhesion and proteoglycan in cancer pathways. Some of these proteins, including CSPG4, which when suppressed by transient siRNA transfection in NSCLC cells resulted in reduced cell viability, were expressed also in EVs from serum of the NSCLC patients. Moreover, PEA profiling of the serum-isolated EVs revealed signatures associated with immune cells, best response and/or progression-free survival, including PD-L1, CD73/NT5E, FR-alpha/FOLR1, LAMP3, FASLG1 and ANXA1. In summary, we demonstrate that protein profiling of EVs in relation to osimertinib refractoriness has the potential to identify possible biomarkers that can indicate osimertinib treatment resistance, for example, CSPG4, HSPG2, TAGLN, TNC, THBS1, ANXA1 and CD73/NT5E. Studies in ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Journal of Extracellular Vesicles, 2026, 15:1; PMID 41581122; ISI:001703794100001 |
| DOI: |
10.1002/jev2.70219 |
| Availability: |
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-582505; https://doi.org/10.1002/jev2.70219 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.FCEB4F1E |
| Database: |
BASE |