2. Academic Validation
  3. Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells

Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells

  • NPJ Precis Oncol. 2021 Jul 15;5(1):65. doi: 10.1038/s41698-021-00208-w.
Mikkel G Terp  # 1,  Kirstine Jacobsen  # 1,  Miguel Angel Molina 2,  Niki Karachaliou 3 4,  Hans C Beck 5,  Jordi Bertran-Alamillo 2,  Ana Giménez-Capitán 2,  Andrés F Cardona 6,  Rafael Rosell 2 7 8 9,  Henrik J Ditzel 10 11 12
Affiliations

Affiliations

  • 1 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.
  • 2 Laboratory of Oncology, Pangaea Biotech, Quiron Dexeus University Hospital, Barcelona, Spain.
  • 3 Instituto Oncológico Dr. Rosell, University Hospital Sagrat Cor, Barcelona, Spain.
  • 4 Global Clinical Development, Merck Healthcare KGaA, Darmstadt, Germany.
  • 5 Center for Clinical Proteomics, Odense University Hospital, Odense C, Denmark.
  • 6 Thoracic Oncology Unit, Clinical and Translational Oncology Group, Clinica del Country, Bogotá, Colombia.
  • 7 Instituto Oncológico Dr. Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain.
  • 8 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
  • 9 Germans Trias i Pujol, Health Sciences Institute and Hospital, Badalona, Spain.
  • 10 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark. [email protected].
  • 11 Department of Oncology, Odense University Hospital, Odense C, Denmark. [email protected].
  • 12 Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, Odense C, Denmark. [email protected].
  • # Contributed equally.
PMID: 34267282 DOI: 10.1038/s41698-021-00208-w
Abstract

EGFR tyrosine kinase inhibitor (TKI) resistance in non-small cell lung Cancer (NSCLC) patients is inevitable. Identification of resistance mechanisms and corresponding targeting strategies can lead to more successful later-line treatment in many patients. Using spectrometry-based proteomics, we identified increased Fibroblast Growth Factor receptor 1 (FGFR1) expression and Akt activation across erlotinib, gefitinib, and osimertinib EGFR-TKI-resistant cell line models. We show that while combined EGFR-TKI and FGFR inhibition showed some efficacy, simultaneous inhibition of FGFR and Akt or PI3K induced superior synergistic growth inhibition of FGFR1-overexpressing EGFR-TKI-resistant NSCLC cells. This effect was confirmed in vivo. Only dual FGFR and Akt inhibition completely blocked the resistance-mediating signaling pathways downstream of Akt. Further, increased FGFR1 expression was associated with significantly lower PFS in EGFR-TKI-treated NSCLC patients, and increased FGFR1 were demonstrated in a few post- vs. pre-EGFR-TKI treatment clinical biopsies. The superior therapeutic benefit of combining FGFR and Akt inhibitors provide the rationale for clinical trials of this strategy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15965
    99.74%, Akt Inhibitor
    Akt