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Identification of therapeutic targets in ovarian cancer through active tyrosine kinase profiling.
- Source :
-
Oncotarget [Oncotarget] 2015 Oct 06; Vol. 6 (30), pp. 30057-71. - Publication Year :
- 2015
-
Abstract
- The activation status of a set of pro-oncogenic tyrosine kinases in ovarian cancer patient samples was analyzed to define potential therapeutic targets. Frequent activation of HER family receptor tyrosine kinases, especially HER2, was observed. Studies in ovarian cancer cell lines confirmed the activation of HER2. Moreover, knockdown of HER2 caused a strong inhibition of their proliferation. Analyses of the action of agents that target HER2 indicated that the antibody drug conjugate trastuzumab-emtansine (T-DM1) caused a substantial antitumoral effect in vivo and in vitro, and potentiated the action of drugs used in the therapy of ovarian cancer. T-DM1 provoked cell cycle arrest in mitosis, and caused the appearance of aberrant mitotic spindles in cells treated with the drug. Biochemical experiments confirmed accumulation of the mitotic markers phospho-Histone H3 and phospho-BUBR1 in cells treated with the drug. Prolonged treatment of ovarian cancer cells with T-DM1 provoked the appearance of multinucleated cells which later led to cell death. Together, these data indicate that HER2 represents an important oncogene in ovarian cancer, and suggest that targeting this tyrosine kinase with T-DM1 may be therapeutically effective, especially in ovarian tumors with high content of HER2.
- Subjects :
- Ado-Trastuzumab Emtansine
Adult
Aged
Animals
Antineoplastic Agents pharmacology
Apoptosis drug effects
Apoptosis genetics
Blotting, Western
Cell Cycle drug effects
Cell Cycle genetics
Cell Line, Tumor
Cell Proliferation drug effects
Cell Proliferation genetics
Female
Humans
Maytansine pharmacology
Mice, Inbred BALB C
Mice, Nude
Microscopy, Fluorescence
Middle Aged
Ovarian Neoplasms metabolism
Ovarian Neoplasms pathology
Proteomics methods
RNA Interference
Receptor, ErbB-2 genetics
Receptor, ErbB-2 metabolism
Trastuzumab
Xenograft Model Antitumor Assays
Antibodies, Monoclonal, Humanized pharmacology
Maytansine analogs & derivatives
Ovarian Neoplasms drug therapy
Receptor, ErbB-2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 6
- Issue :
- 30
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26336133
- Full Text :
- https://doi.org/10.18632/oncotarget.4996