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Ref Type Journal Article
PMID (30537101)
Authors Packer LM, Stehbens SJ, Bonazzi VF, Gunter JH, Ju RJ, Ward M, Gartside MG, Byron SA, Pollock PM
Title Bcl-2 inhibitors enhance FGFR inhibitor-induced mitochondrial-dependent cell death in FGFR2-mutant endometrial cancer.
Journal Molecular oncology
Vol 13
Issue 4
Date 2019 04
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 N550K endometrial cancer predicted - sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 treatment induced cell death in an endometrial cancer cell line harboring FGFR2 N550K in culture (PMID: 30537101). 30537101
FGFR2 N550K endometrial cancer predicted - sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment induced cell death in an endometrial cancer cell line harboring FGFR2 N550K in culture (PMID: 30537101). 30537101
FGFR2 K310R FGFR2 N550K endometrial cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 treatment induced cell death and reduced survival of an endometrial cancer cell line harboring FGFR2 N550K and K310R in culture (PMID: 30537101). 30537101
FGFR2 C383R endometrial cancer sensitive PD173074 Preclinical - Cell culture Actionable In a preclinical study, PD173074 treatment induced cell death and reduced survival of an endometrial cancer cell line harboring FGFR2 C383R in culture (PMID: 30537101). 30537101
FGFR2 C383R endometrial cancer sensitive ABT-737 + Infigratinib Preclinical - Cell culture Actionable In a preclinical study, an endometrial cancer cell line harboring FGFR2 C383R demonstrated increased cell death following treatment with Truseltiq (infigratinib) and ABT-737 combination compared to either agent alone in culture (PMID: 30537101). 30537101
FGFR2 C383R endometrial cancer sensitive ABT-737 + PD173074 Preclinical - Cell culture Actionable In a preclinical study, an endometrial cancer cell line harboring FGFR2 C383R demonstrated increased cell death following treatment with PD173074 and ABT-737 combination compared to either agent alone in culture (PMID: 30537101). 30537101
FGFR2 K310R FGFR2 N550K endometrial cancer sensitive Infigratinib + Navitoclax Preclinical - Cell line xenograft Actionable In a preclinical study, Truseltiq (infigratinib) and Navitoclax (ABT-263) combination treatment enhanced apoptosis, and inhibited tumor growth and induced regression in a cell line xenograft model of endometrial cancer harboring FGFR2 K310R and N550K compared to either agent alone (PMID: 30537101). 30537101
FGFR2 K310R FGFR2 N550K endometrial cancer sensitive Infigratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Truseltiq (infigratinib) treatment induced cell death and reduced survival of an endometrial cancer cell line harboring FGFR2 N550K and K310R in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 30537101). 30537101
FGFR2 K310R FGFR2 N550K endometrial cancer sensitive ABT-737 + AZD4547 Preclinical - Cell culture Actionable In a preclinical study, an endometrial cancer cell line harboring FGFR2 N550K and K310R demonstrated increased cell death following treatment with AZD4547 and ABT-737 combination compared to either agent alone in culture (PMID: 30537101). 30537101
FGFR2 K310R FGFR2 N550K endometrial cancer sensitive ABT-737 + Infigratinib Preclinical - Cell culture Actionable In a preclinical study, an endometrial cancer cell line harboring FGFR2 N550K and K310R demonstrated increased cell death following treatment with Truseltiq (infigratinib) and ABT-737 combination compared to either agent alone in culture (PMID: 30537101). 30537101
FGFR2 N550K endometrial cancer sensitive ABT-737 + AZD4547 Preclinical - Cell culture Actionable In a preclinical study, an endometrial cancer cell line harboring FGFR2 N550K demonstrated increased cell death following treatment with AZD4547 and ABT-737 combination compared to either agent alone in culture (PMID: 30537101). 30537101
FGFR2 C383R endometrial cancer sensitive ABT-737 + AZD4547 Preclinical - Cell culture Actionable In a preclinical study, an endometrial cancer cell line harboring FGFR2 C383R demonstrated increased cell death following treatment with AZD4547 and ABT-737 combination compared to either agent alone in culture (PMID: 30537101). 30537101
FGFR2 C383R endometrial cancer sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment induced cell death and reduced survival of an endometrial cancer cell line harboring FGFR2 C383R in culture (PMID: 30537101). 30537101
FGFR2 N550K endometrial cancer sensitive ABT-737 + PD173074 Preclinical - Cell culture Actionable In a preclinical study, an endometrial cancer cell line harboring FGFR2 N550K demonstrated increased cell death following treatment with PD173074 and ABT-737 combination compared to either agent alone in culture (PMID: 30537101). 30537101
FGFR2 N550K endometrial cancer sensitive ABT-737 + Infigratinib Preclinical - Cell culture Actionable In a preclinical study, an endometrial cancer cell line harboring FGFR2 N550K demonstrated increased cell death following treatment with Truseltiq (infigratinib) and ABT-737 combination compared to either agent alone in culture (PMID: 30537101). 30537101
FGFR2 C383R endometrial cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 treatment induced cell death and reduced survival of an endometrial cancer cell line harboring FGFR2 C383R in culture (PMID: 30537101). 30537101
FGFR2 N550K endometrial cancer predicted - sensitive PD173074 Preclinical - Cell culture Actionable In a preclinical study, PD173074 treatment induced cell death in an endometrial cancer cell line harboring FGFR2 N550K in culture (PMID: 30537101). 30537101
FGFR2 K310R FGFR2 N550K endometrial cancer sensitive PD173074 Preclinical - Cell culture Actionable In a preclinical study, PD173074 treatment induced cell death and reduced survival of an endometrial cancer cell line harboring FGFR2 N550K and K310R in culture (PMID: 30537101). 30537101
FGFR2 K310R FGFR2 N550K endometrial cancer sensitive ABT-737 + PD173074 Preclinical - Cell culture Actionable In a preclinical study, an endometrial cancer cell line harboring FGFR2 N550K and K310R demonstrated increased cell death following treatment with PD173074 and ABT-737 combination compared to either agent alone in culture (PMID: 30537101). 30537101