EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen.
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.
University College London Cancer Institute, London, UK.|Department of Orthopaedics and Orthopaedic Surgery, Medical University of Graz, Austria.
Susanne
S
Scheipl
University College London Cancer Institute, London, UK.|Cancer Research Technology Discovery Laboratories, Cambridge, UK.|CRUK-MedImmune Alliance Laboratory, Cambridge, UK.
Michelle
M
Barnard
University College London Cancer Institute, London, UK.
Lucia
L
Cottone
University College London Cancer Institute, London, UK.
Mette
M
Jorgensen
GlaxoSmithKline, Research Triangle Park, NC, USA.|SGC-UNC, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, USA.
David H
DH
Drewry
GlaxoSmithKline, Research Triangle Park, NC, USA.|SGC-UNC, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, USA.
William J
WJ
Zuercher
Cancer Research Technology Discovery Laboratories, Cambridge, UK.
Fabrice
F
Turlais
Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, UK.
Hongtao
H
Ye
University College London Cancer Institute, London, UK.
Ana P
AP
Leite
Cancer Research Technology Discovery Laboratories, Cambridge, UK.
James A
JA
Smith
Department of Orthopaedics and Orthopaedic Surgery, Medical University of Graz, Austria.
Andreas
A
Leithner
Institute of Pathology, Ulm University, Germany.
Peter
P
Möller
Institute of Pathology, Ulm University, Germany.
Silke
S
Brüderlein
University College London Advanced Diagnostics, London, UK.
Naomi
N
Guppy
Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, UK.
Fernanda
F
Amary
Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, UK.
Roberto
R
Tirabosco
University College London Cancer Institute, London, UK.
Sandra J
SJ
Strauss
University College London Cancer Institute, London, UK.|Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, UK.
Nischalan
N
Pillay
University College London Cancer Institute, London, UK.|Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, UK.|University College London Advanced Diagnostics, London, UK.
Adrienne M
AM
Flanagan
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002817:Chordoma / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D000077156:Gefitinib; D006801:Humans; D051379:Mice; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
C548875:AZD 8931; D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
AZD8931; EGFR; ERBB family; chordoma; drug screen; resistance