RRC ID 54768
著者 Packer LM, Stehbens SJ, Bonazzi VF, Gunter JH, Ju RJ, Ward M, Gartside MG, Byron SA, Pollock PM.
タイトル Bcl-2 inhibitors enhance FGFR inhibitor-induced mitochondrial-dependent cell death in FGFR2-mutant endometrial cancer.
ジャーナル Mol Oncol
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.
巻・号 13(4)
ページ 738-756
公開日 2019-4-1
DOI 10.1002/1878-0261.12422
PMID 30537101
PMC PMC6441928
MeSH Animals Apoptosis* Autophagosomes / metabolism Caspases / metabolism Cell Line, Tumor Endometrial Neoplasms / genetics* Endometrial Neoplasms / pathology* Enzyme Activation Female Humans Inhibitory Concentration 50 Mice Mitochondria / metabolism* Mutation / genetics* Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors* Proto-Oncogene Proteins c-bcl-2 / metabolism Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors* Receptor, Fibroblast Growth Factor, Type 2 / metabolism
IF 5.962
引用数 2
リソース情報
ヒト・動物細胞 JHUEM-2(RCB1551)