TY - JOUR
T1 - AZD8055 enhances in vivo efficacy of afatinib in chordomas
AU - Zhao, Tianna
AU - Siu, I. Mei
AU - Williamson, Tara
AU - Zhang, Haoyu
AU - Ji, Chenchen
AU - Burger, Peter C.
AU - Connis, Nick
AU - Ruzevick, Jacob
AU - Xia, Menghang
AU - Cottone, Lucia
AU - Flanagan, Adrienne M.
AU - Hann, Christine L.
AU - Gallia, Gary L.
N1 - Funding Information:
The U-CH1 and U-CH2 cell lines were kindly provided by the Chordoma Foundation; the JHC7 cell line was kindly provided by Alfredo Quiñones-Hinojosa; and idarubicin, SAHA, staurosporine, and 17-AAG were kindly provided by NCATS. We would like to thank Josh Sommer and the Chordoma Foundation for their support and assistance. We thank past and present members of the Skull Base and Hunterian Neurosurgical Research Laboratories. We are grateful to our patients for their courage and generosity and thank the biobank team for consenting patients and accessing samples. This study was supported by the Chordoma Foundation, Johns Hopkins University School of Medicine Department of Neurosurgery, and Michael and Noreen Potempa (to GLG) and Chordoma UK, the Skeletal Cancer Trust, the Royal National Orthopaedic Hospital NHS Trust R&D Programme, the National Institute for Health Research UCLH Biomedical Research Centre, and the UCL Experimental Cancer Centre (to AMF). This work was also supported in part by the Intramural Research Program of the NCATS, NIH (to MX). LC was funded by the Chordoma Foundation. CLH is supported by NIH grant 1U01CA231776.
Funding Information:
The U‐CH1 and U‐CH2 cell lines were kindly provided by the Chordoma Foundation; the JHC7 cell line was kindly provided by Alfredo Quiñones‐Hinojosa; and idarubicin, SAHA, staurosporine, and 17‐AAG were kindly provided by NCATS. We would like to thank Josh Sommer and the Chordoma Foundation for their support and assistance. We thank past and present members of the Skull Base and Hunterian Neurosurgical Research Laboratories. We are grateful to our patients for their courage and generosity and thank the biobank team for consenting patients and accessing samples. This study was supported by the Chordoma Foundation, Johns Hopkins University School of Medicine Department of Neurosurgery, and Michael and Noreen Potempa (to GLG) and Chordoma UK, the Skeletal Cancer Trust, the Royal National Orthopaedic Hospital NHS Trust R&D Programme, the National Institute for Health Research UCLH Biomedical Research Centre, and the UCL Experimental Cancer Centre (to AMF). This work was also supported in part by the Intramural Research Program of the NCATS, NIH (to MX). LC was funded by the Chordoma Foundation. CLH is supported by NIH grant 1U01CA231776.
Publisher Copyright:
© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
PY - 2021/9
Y1 - 2021/9
N2 - Chordomas are primary bone tumors that arise in the cranial base, mobile spine, and sacrococcygeal region, affecting patients of all ages. Currently, there are no approved agents for chordoma patients. Here, we evaluated the anti-tumor efficacy of small molecule inhibitors that target oncogenic pathways in chordoma, as single agents and in combination, to identify novel therapeutic approaches with the greatest translational potential. A panel of small molecule compounds was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and potentially synergistic combinations were further evaluated using chordoma cell lines and xenograft models. Among the tested agents, inhibitors of EGFR (BIBX 1382, erlotinib, and afatinib), c-MET (crizotinib), and mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, this dual inhibition completely suppressed tumor growth in vivo, showing improved tumor control. Together, these data demonstrate that individual inhibitors of EGFR, c-MET, and mTOR pathways suppress chordoma growth both in vitro and in vivo. mTOR inhibition increased the efficacy of EGFR inhibition on chordoma growth in several preclinical models. The insights gained from our study potentially provide a novel combination therapeutic strategy for patients with chordoma.
AB - Chordomas are primary bone tumors that arise in the cranial base, mobile spine, and sacrococcygeal region, affecting patients of all ages. Currently, there are no approved agents for chordoma patients. Here, we evaluated the anti-tumor efficacy of small molecule inhibitors that target oncogenic pathways in chordoma, as single agents and in combination, to identify novel therapeutic approaches with the greatest translational potential. A panel of small molecule compounds was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and potentially synergistic combinations were further evaluated using chordoma cell lines and xenograft models. Among the tested agents, inhibitors of EGFR (BIBX 1382, erlotinib, and afatinib), c-MET (crizotinib), and mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, this dual inhibition completely suppressed tumor growth in vivo, showing improved tumor control. Together, these data demonstrate that individual inhibitors of EGFR, c-MET, and mTOR pathways suppress chordoma growth both in vitro and in vivo. mTOR inhibition increased the efficacy of EGFR inhibition on chordoma growth in several preclinical models. The insights gained from our study potentially provide a novel combination therapeutic strategy for patients with chordoma.
KW - EGFR
KW - chordomas
KW - mTOR
KW - preclinical models
KW - small molecule inhibitors
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U2 - 10.1002/path.5739
DO - 10.1002/path.5739
M3 - Article
C2 - 34124783
AN - SCOPUS:85111385552
SN - 0022-3417
VL - 255
SP - 72
EP - 83
JO - Journal of Pathology
JF - Journal of Pathology
IS - 1
ER -