In:
Molecular Oncology, Wiley, Vol. 13, No. 4 ( 2019-04), p. 738-756
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 ( FGFR 2) in 12% (stage I/ II ) to 17% (stage III / IV ) endometrioid EC s 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 BGJ 398, AZD 4547 and PD 173074 causes mitochondrial depolarization, cytochrome c release and impaired mitochondrial respiration in two FGFR 2‐mutant EC cell lines ( AN 3 CA and JHUEM 2). 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 LC 3 puncta, treatment with bafilomycin did not further increase lipidated LC 3, 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 BH 3 mimetics ABT 737/ ABT 263 markedly increased cell death in vitro and is more effective than BGJ 398 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.
Type of Medium:
Online Resource
ISSN:
1574-7891
,
1878-0261
DOI:
10.1002/mol2.2019.13.issue-4
DOI:
10.1002/1878-0261.12422
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2322586-5
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