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Sci Rep. 2019 Jan 15;9(1):139. doi: 10.1038/s41598-018-37437-2.

Genetically distinct glioma stem-like cell xenografts established from paired glioblastoma samples harvested before and after molecularly targeted therapy.

Author information

1
Divisions of Neuro-Oncology and Hematology/Oncology, Harvard Medical School, Boston, Massachusetts, USA. tanakas-tky@umin.ac.jp.
2
Department of Neurosurgery, The University of Tokyo Hospital, Tokyo, Japan. tanakas-tky@umin.ac.jp.
3
Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
5
Center for Stem Cell Therapeutics and Imaging, Department of Neurosurgery, Brigham and Women's Hospital, Harvard medical School, Boston, Massachusetts, USA.
6
Divisions of Neuro-Oncology and Hematology/Oncology, Harvard Medical School, Boston, Massachusetts, USA.
7
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health and NYU School of Medicine, New York, NY, USA.
8
Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts, USA. hwakimoto@mgh.harvard.edu.

Abstract

Intratumoural heterogeneity underlies tumour escape from molecularly targeted therapy in glioblastoma. A cell-based model preserving the evolving molecular profiles of a tumour during treatment is key to understanding the recurrence mechanisms and development of strategies to overcome resistance. In this study, we established a matched pair of glioblastoma stem-like cell (GSC) cultures from patient glioblastoma samples before and after epidermal growth factor receptor (EGFR)-targeted therapy. A patient with recurrent glioblastoma (MGG70R) harboring focal, high-level EGFR amplification received the irreversible EGFR tyrosine kinase inhibitor dacomitinib. The tumour that subsequently recurred (MGG70RR) showed diploid EGFR, suggesting inhibitor-mediated elimination of EGFR-amplified tumour cells and propagation of EGFR non-amplified cell subpopulations. The MGG70R-GSC line established from MGG70R formed xenografts retaining EGFR amplification and EGFR overexpression, while MGG70RR-GSC established from MGG70RR generated tumours that lacked EGFR amplification and EGFR overexpression. MGG70R-GSC-derived intracranial xenografts were more proliferative than MGG70RR-GSC xenografts, which had upregulated mesenchymal markers, mirroring the pathological observation in the corresponding patient tumours. In vitro MGG70R-GSC was more sensitive to EGFR inhibitors than MGG70RR-GSC. Thus, these molecularly distinct GSC lines recapitulated the subpopulation alteration that occurred during glioblastoma evasion of targeted therapy, and offer a valuable model facilitating therapeutic development for recurrent glioblastoma.

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