Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular oncology	13	4	2019 04	738-756	Mol Oncol

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 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 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 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 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 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 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	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 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 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 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 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 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 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	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 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 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 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
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