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Crizotinib targets in glioblastoma stem cells.
- Source :
-
Cancer medicine [Cancer Med] 2017 Nov; Vol. 6 (11), pp. 2625-2634. Date of Electronic Publication: 2017 Sep 27. - Publication Year :
- 2017
-
Abstract
- Glioblastoma stem cells (GSCs) are believed to be involved in the mechanisms of tumor resistance, therapeutic failures, and recurrences after conventional glioblastoma therapy. Therefore, elimination of GSCs might be a prerequisite for the development of successful therapeutic strategies. ALK, ROS1, and MET are targeted by Crizotinib, a tyrosine kinase inhibitor which has been approved for treatment of ALK-rearranged non-small-cell lung cancer. In this study we investigated ALK, ROS1, and MET status in nine glioblastoma stem cell lines and tumors from which they arise. Fluorescent in situ hybridization (FISH), Sanger's direct sequencing, and immunohistochemistry were used to screen genomic rearrangements (or amplifications), genomic mutations, and protein expression, respectively. The immunohistochemical and FISH studies revealed no significant dysregulation of ROS1 in GSCs and associated tumors. Neither amplification nor polysomy of ALK was observed in GSC, but weak overexpression was detected by IHC in three of nine GSCs. Similarly, no MET amplification was found by FISH but three GSCs presented significant immunohistochemical staining. No ALK or MET mutation was found by Sanger's direct sequencing. In this study, we show no molecular rearrangement of ALK, ROS1, and MET that would lead us not to propose, as a valid strategy, the use of crizotinib to eradicate GSCs. However, MET was overexpressed in all GSCs with mesenchymal subtype and three GSCs presented an overexpression of ALK. Therefore, our study corroborates the idea that MET and ALK may assume a role in the tumorigenicity of GSC.<br /> (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Subjects :
- Aged
Anaplastic Lymphoma Kinase
Cell Line, Tumor
Central Nervous System Neoplasms genetics
Central Nervous System Neoplasms metabolism
Crizotinib
DNA Mutational Analysis
Female
Glioblastoma genetics
Glioblastoma metabolism
Humans
Male
Middle Aged
Molecular Targeted Therapy
Neoplastic Stem Cells metabolism
Pyrazoles metabolism
Pyridines metabolism
Central Nervous System Neoplasms drug therapy
Glioblastoma drug therapy
Protein Kinase Inhibitors therapeutic use
Protein-Tyrosine Kinases genetics
Protein-Tyrosine Kinases metabolism
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-met genetics
Proto-Oncogene Proteins c-met metabolism
Pyrazoles therapeutic use
Pyridines therapeutic use
Receptor Protein-Tyrosine Kinases genetics
Receptor Protein-Tyrosine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2045-7634
- Volume :
- 6
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer medicine
- Publication Type :
- Academic Journal
- Accession number :
- 28960893
- Full Text :
- https://doi.org/10.1002/cam4.1167