{"doi":"10.1007/s13402-021-00632-x","title":"Drug combination screening as a translational approach toward an improved drug therapy for chordoma","abstract":"Abstract 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.","journal":"Cellular Oncology","year":2021,"id":194199,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":763457,"name":"Michelle Barnard","orcid":"0000-0001-9668-3288","position":1,"is_corresponding":false},{"id":763458,"name":"Birgit Lohberger","orcid":"0000-0002-3156-7902","position":2,"is_corresponding":false},{"id":764001,"name":"Richard Zettl","orcid":null,"position":3,"is_corresponding":false},{"id":763459,"name":"Iva Brčić","orcid":"0000-0001-9847-0171","position":4,"is_corresponding":false},{"id":763460,"name":"Bernadette Liegl‐Atzwanger","orcid":"0000-0003-2229-5535","position":5,"is_corresponding":false},{"id":763461,"name":"Beate Rinner","orcid":"0000-0002-6340-4905","position":6,"is_corresponding":false},{"id":764002,"name":"Claudia Meindl","orcid":null,"position":7,"is_corresponding":false},{"id":763462,"name":"Eleonore Fröhlich","orcid":"0000-0002-6056-6829","position":8,"is_corresponding":false},{"id":763456,"name":"Susanne Scheipl","orcid":"0000-0002-6675-7052","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-18T23:49:55.282992Z","pmid":"34550531","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}