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Bcl-2 inhibitors enhance FGFR inhibitor-induced mitochondrial-dependent cell death in FGFR2-mutant endometrial cancer.
- Source :
-
Molecular oncology [Mol Oncol] 2019 Apr; Vol. 13 (4), pp. 738-756. Date of Electronic Publication: 2019 Jan 18. - Publication Year :
- 2019
-
Abstract
- Endometrial cancer is the most commonly diagnosed gynaecological malignancy. Unfortunately, 15-20% of women demonstrate persistent or recurrent tumours that are refractory to current chemotherapies. We previously identified activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 12% (stage I/II) to 17% (stage III/IV) endometrioid ECs and found that these mutations are associated with shorter progression-free and cancer-specific survival. Although FGFR inhibitors are undergoing clinical trials for treatment of several cancer types, little is known about the mechanism by which they induce cell death. We show that treatment with BGJ398, AZD4547 and PD173074 causes mitochondrial depolarization, cytochrome c release and impaired mitochondrial respiration in two FGFR2-mutant EC cell lines (AN3CA and JHUEM2). Despite this mitochondrial dysfunction, we were unable to detect caspase activation following FGFR inhibition; in addition, the pan-caspase inhibitor Z-VAD-FMK was unable to prevent cell death, suggesting that the cell death is caspase-independent. Furthermore, while FGFR inhibition led to an increase in LC3 puncta, treatment with bafilomycin did not further increase lipidated LC3, suggesting that FGFR inhibition led to a block in autophagosome degradation. We confirmed that cell death is mitochondrial-dependent as it can be blocked by overexpression of Bcl-2 and/or Bcl-XL. Importantly, we show that combining FGFR inhibitors with the BH3 mimetics ABT737/ABT263 markedly increased cell death in vitro and is more effective than BGJ398 alone in vivo, where it leads to marked tumour regression. This work may have implications for the design of clinical trials to treat a wide range of patients with FGFR-dependent malignancies.<br /> (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
- Subjects :
- Animals
Autophagosomes metabolism
Caspases metabolism
Cell Line, Tumor
Enzyme Activation
Female
Humans
Inhibitory Concentration 50
Mice
Proto-Oncogene Proteins c-bcl-2 metabolism
Receptor, Fibroblast Growth Factor, Type 2 metabolism
Apoptosis
Endometrial Neoplasms genetics
Endometrial Neoplasms pathology
Mitochondria metabolism
Mutation genetics
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0261
- Volume :
- 13
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular oncology
- Publication Type :
- Academic Journal
- Accession number :
- 30537101
- Full Text :
- https://doi.org/10.1002/1878-0261.12422