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We undertook a focused compound screen (FCS) against 1097 compounds on three well\u2010characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 \u00b5<jats:sc>m<\/jats:sc>), based on their growth\u2010inhibitory effect. Their half\u2010maximal effective concentration (EC<jats:sub>50<\/jats:sub>) values were determined in chordoma cells and normal fibroblasts. Twenty\u2010seven of these compounds displayed chordoma selective cell kill and 21\/27 (78%) were found to be EGFR\/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche\/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho\u2010EGFR and its downstream pathways in a dose\u2010dependent manner. Analysis of substituent patterns suggested that EGFR\u2010inhibitors with small aniline substituents in the 4\u2010position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U\u2010CH1 xenograft and a patient\u2010derived xenograft, SF8894). One of the resistant cell lines (U\u2010CH2) was shown to express high levels of phospho\u2010MET, a known bypass signalling pathway to EGFR. Neither amplifications (<jats:italic>EGFR<\/jats:italic>, <jats:italic>ERBB2<\/jats:italic>, <jats:italic>MET<\/jats:italic>) nor mutations in <jats:italic>EGFR<\/jats:italic>, <jats:italic>ERBB2<\/jats:italic>, <jats:italic>ERBB4<\/jats:italic>, <jats:italic>PIK3CA<\/jats:italic>, <jats:italic>BRAF<\/jats:italic>, <jats:italic>NRAS<\/jats:italic>, <jats:italic>KRAS<\/jats:italic>, <jats:italic>PTEN<\/jats:italic>, <jats:italic>MET<\/jats:italic> or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p\u2010)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. \u00a9 2016 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.4729","type":"journal-article","created":{"date-parts":[[2016,4,22]],"date-time":"2016-04-22T17:40:10Z","timestamp":1461346810000},"page":"320-334","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen"],"prefix":"10.1002","volume":"239","author":[{"given":"Susanne","family":"Scheipl","sequence":"first","affiliation":[{"name":"University College London Cancer Institute  London UK"},{"name":"Department of Orthopaedics and Orthopaedic Surgery Medical University of Graz  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Barnard","sequence":"additional","affiliation":[{"name":"University College London Cancer Institute  London UK"},{"name":"Cancer Research Technology Discovery Laboratories  Cambridge UK"},{"name":"CRUK\u2013MedImmune Alliance Laboratory  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Cottone","sequence":"additional","affiliation":[{"name":"University College London Cancer Institute  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette","family":"Jorgensen","sequence":"additional","affiliation":[{"name":"University College London Cancer Institute  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