Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Scheipl, S; Barnard, M; Lohberger, B; Zettl, R; Brcic, I; Liegl-Atzwanger, B; Rinner, B; Meindl, C; Fröhlich, E.
Drug combination screening as a translational approach toward an improved drug therapy for chordoma.
Cell Oncol (Dordr). 2021; 44(6):1231-1242
Doi: 10.1007/s13402-021-00632-x
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- Führende Autor*innen der Med Uni Graz
- Lohberger Birgit
- Scheipl Susanne
- Co-Autor*innen der Med Uni Graz
- Brcic Iva
- Fröhlich Eleonore
- Liegl-Atzwanger Bernadette
- Meindl Claudia
- Rinner Beate
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- Abstract:
- PURPOSE: Drug screening programmes have revealed epidermal growth factor receptor inhibitors (EGFRis) as promising therapeutics for chordoma, an orphan malignant bone tumour, in the absence of a known genetic driver. Concurrently, the irreversible EGFRi afatinib (Giotrif®) is being evaluated in a multicentric Phase II trial. As tyrosine kinase inhibitor (TKI) monotherapies are invariably followed by resistance, we aimed to evaluate potential therapeutic combinations with EGFRis. METHODS: We screened 133 clinically approved anticancer drugs as single agents and in combination with two EGFRis (afatinib and erlotinib) in the clival chordoma cell line UM-Chor1. Synergistic combinations were analysed in a 7 × 7 matrix format. The most promising combination was further explored in clival (UM-Chor1, MUG-CC1) and sacral (MUG-Chor1, U-CH1) chordoma cell lines. Secretomes were analysed for receptor tyrosine kinase ligands (EGF, TGF-α, FGF-2 and VEGF-A) upon drug treatment. RESULTS: Drugs that were active as single agents (n = 45) included TKIs, HDAC and proteasome inhibitors, and cytostatic drugs. Six combinations were analysed in a matrix format: n = 4 resulted in a significantly increased cell killing (crizotinib, dabrafenib, panobinostat and doxorubicin), and n = 2 exhibited no or negligible effects (regorafenib, venetoclax). Clival chordoma cell lines were more responsive to combined EGFR-MET inhibition. EGFR-MET cross-talk (e.g. via TGF-α secretion) likely accounts for the synergistic effects of EGFR-MET inhibition. CONCLUSION: Our screen revealed promising combinations with EGFRis, such as the ALK/MET-inhibitor crizotinib, the HDAC-inhibitor panobinostat or the topoisomerase-II-inhibitor doxorubicin, which are part of standard chemotherapy regimens for various bone and soft-tissue sarcomas.
- Find related publications in this database (using NLM MeSH Indexing)
- Afatinib - pharmacology, therapeutic use
- Antineoplastic Agents - pharmacology, therapeutic use
- Antineoplastic Combined Chemotherapy Protocols - pharmacology, therapeutic use
- Autocrine Communication - administration & dosage
- Cell Line, Tumor - administration & dosage
- Chordoma - drug therapy
- Crizotinib - pharmacology, therapeutic use
- Drug Approval - administration & dosage
- Drug Screening Assays, Antitumor - administration & dosage
- ErbB Receptors - antagonists & inhibitors, metabolism
- Hepatocyte Growth Factor - metabolism
- Humans - administration & dosage
- Ligands - administration & dosage
- Protein Kinase Inhibitors - pharmacology
- Proto-Oncogene Proteins c-met - metabolism
- Transforming Growth Factor alpha - metabolism
- Translational Research, Biomedical - administration & dosage
- United States - administration & dosage
- United States Food and Drug Administration - administration & dosage
- Vascular Endothelial Growth Factor A - metabolism
- Find related publications in this database (Keywords)
- Bone tumour
- Chordoma
- Precision medicine
- Targeted therapy
- EGFR inhibitor
- Combination screen