Drug combination screening as a translational approach toward an improved drug therapy for chordoma.

Publisher: Springer Country of Publication: Netherlands NLM ID: 101552938 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-3436 (Electronic) Linking ISSN: 22113428 NLM ISO Abbreviation: Cell Oncol (Dordr) Subsets: MEDLINE

Original Publication: Dordrecht : Springer

Drug Screening Assays, Antitumor* ; Translational Research, Biomedical*; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Chordoma/*drug therapy; Afatinib/pharmacology ; Afatinib/therapeutic use ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Autocrine Communication ; Cell Line, Tumor ; Crizotinib/pharmacology ; Crizotinib/therapeutic use ; Drug Approval ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/metabolism ; Hepatocyte Growth Factor/metabolism ; Humans ; Ligands ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-met/metabolism ; Transforming Growth Factor alpha/metabolism ; United States ; United States Food and Drug Administration ; Vascular Endothelial Growth Factor A/metabolism

Purpose: Drug screening programmes have revealed epidermal growth factor receptor inhibitors (EGFR i s) as promising therapeutics for chordoma, an orphan malignant bone tumour, in the absence of a known genetic driver. Concurrently, the irreversible EGFR i 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 EGFR i s.
Methods: We screened 133 clinically approved anticancer drugs as single agents and in combination with two EGFR i s (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 EGFR i s, 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.
(© 2021. The Author(s).)

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ISNK2017 Ingrid Shaker Nessmann Cancer Research Association

Keywords: Bone tumour; Chordoma; Combination screen; EGFR inhibitor; Precision medicine; Targeted therapy

0 (Antineoplastic Agents)
0 (Ligands)
0 (Protein Kinase Inhibitors)
0 (Transforming Growth Factor alpha)
0 (Vascular Endothelial Growth Factor A)
41UD74L59M (Afatinib)
53AH36668S (Crizotinib)
67256-21-7 (Hepatocyte Growth Factor)
EC 2.7.10.1 (ErbB Receptors)
EC 2.7.10.1 (Proto-Oncogene Proteins c-met)

Date Created: 20210922 Date Completed: 20220308 Latest Revision: 20220829

20240829

PMC8648636

10.1007/s13402-021-00632-x

34550531