EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen |
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| Authors: | Susanne Scheipl Michelle Barnard Lucia Cottone Mette Jorgensen David H Drewry William J Zuercher Fabrice Turlais Hongtao Ye Ana P Leite James A Smith Andreas Leithner Peter Möller Silke Brüderlein Naomi Guppy Fernanda Amary Roberto Tirabosco Sandra J Strauss Nischalan Pillay Adrienne M Flanagan |
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| Affiliation: | 1. University College London Cancer Institute, London, UK;2. Department of Orthopaedics and Orthopaedic Surgery, Medical University of Graz, Austria;3. Cancer Research Technology Discovery Laboratories, Cambridge, UK;4. CRUK–MedImmune Alliance Laboratory, Cambridge, UK;5. GlaxoSmithKline, Research Triangle Park, NC, USA;6. SGC–UNC, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, USA;7. Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, UK;8. Institute of Pathology, Ulm University, Germany;9. University College London Advanced Diagnostics, London, UK |
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| Abstract: | Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well‐characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm ), based on their growth‐inhibitory effect. Their half‐maximal effective concentration (EC50) values were determined in chordoma cells and normal fibroblasts. Twenty‐seven 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‐EGFR and its downstream pathways in a dose‐dependent manner. Analysis of substituent patterns suggested that EGFR‐inhibitors with small aniline substituents in the 4‐position 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‐CH1 xenograft and a patient‐derived xenograft, SF8894). One of the resistant cell lines (U‐CH2) was shown to express high levels of phospho‐MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p‐)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 in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
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| Keywords: | chordoma drug screen EGFR ERBB family AZD8931 resistance |
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