PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutant Endometrial Cancers

Packer, Leisl; Geng, Xiaojun; Bonazzi, Vanessa; Ju, Robert J.; Mahon, Clare E.; Cummings, Margaret C.; Stephenson, Sally‐Anne; Pollock, Pamela M.

doi:10.1158/1535-7163.mct-16-0415

Cited by 37 publications

(30 citation statements)

References 47 publications

(28 reference statements)

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“…D–E; P < 0.0001). This is consistent with in vivo results showing reduction in tumour growth in AN3CA and JHUEM2 cells treated with BGJ398 (Packer et al ., ).…”

Section: Resultsmentioning

confidence: 97%

“…FGFR2 immunoprecipitation was performed as described in Packer et al . (). Bim IP was performed as described in Packer et al .…”

Section: Methodsmentioning

confidence: 97%

“…Bim IP was performed as described in Packer et al . (). Normalized IP fold changes were calculated as follows:

\frac{Interacting {protein}_{normaltreatment}}{{Bim}_{normaltreatment} \div {Bim}_{normalDMSO}} \div \frac{Interacting {protein}_{normalDMSO}}{{Bim}_{normalDMSO} \div {Bim}_{normalDMSO}}

…”

Section: Methodsmentioning

confidence: 97%

“…To stimulate FGFR2, cells were treated with 10 ngÁmL À1 FGF10 (R&D systems, Noble Park, VIC, Australia) and 5 lgÁmL À1 heparin (Sigma) for 10 min prior to collection of lysate. FGFR2 immunoprecipitation was performed as described in Packer et al (2017). Bim IP was performed as described in Packer et al (2017).…”

Section: Western Blot Immunoprecipitation and Antibodiesmentioning

confidence: 99%

“…FGFR2 immunoprecipitation was performed as described in Packer et al (2017). Bim IP was performed as described in Packer et al (2017). Normalized IP fold changes were calculated as follows:…”

Section: Western Blot Immunoprecipitation and Antibodiesmentioning

confidence: 99%

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Bcl‐2 inhibitors enhance FGFR inhibitor‐induced mitochondrial‐dependent cell death in FGFR2‐mutant endometrial cancer

et al. 2019

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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.

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“…D–E; P < 0.0001). This is consistent with in vivo results showing reduction in tumour growth in AN3CA and JHUEM2 cells treated with BGJ398 (Packer et al ., ).…”

Section: Resultsmentioning

confidence: 97%

“…FGFR2 immunoprecipitation was performed as described in Packer et al . (). Bim IP was performed as described in Packer et al .…”

Section: Methodsmentioning

confidence: 97%

“…Bim IP was performed as described in Packer et al . (). Normalized IP fold changes were calculated as follows:

\frac{Interacting {protein}_{normaltreatment}}{{Bim}_{normaltreatment} \div {Bim}_{normalDMSO}} \div \frac{Interacting {protein}_{normalDMSO}}{{Bim}_{normalDMSO} \div {Bim}_{normalDMSO}}

…”

Section: Methodsmentioning

confidence: 97%

Section: Western Blot Immunoprecipitation and Antibodiesmentioning

confidence: 99%

Section: Western Blot Immunoprecipitation and Antibodiesmentioning

confidence: 99%

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Bcl‐2 inhibitors enhance FGFR inhibitor‐induced mitochondrial‐dependent cell death in FGFR2‐mutant endometrial cancer

et al. 2019

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Critical role of HOX transcript antisense intergenic RNA (HOTAIR) in gliomas

2020

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Lenvatinib inhibits intrahepatic cholangiocarcinoma via Gadd45a-mediated cell cycle arrest

et al. 2023

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Purpose To evaluate the anticancer activities of lenvatinib in ICC and its possible molecular mechanisms. Methods Patients-derived xenograft (PDX) model and cell line-derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyze the effect of Lenvatinib on cell proliferation, cell cycle progression, apoptosis, and the molecular mechanism. Results In the present study, we found that lenvatinib dramatically hindered in vivo tumor growth in ICC patient-derived xenograft models. In addition, by using in vitro experiments in ICC cell lines, we found that lenvatinib dose- and time-dependently inhibited the proliferation of ICC cells and induced cell cycle arrest in the G0/G1 phase. Transcriptional profiling analysis further applied indicated that lenvatinib might inhibit cell proliferation through the induction of cell-cycle arrestment via activating of Gadd45a, it was evidenced by that the knockout of Gadd45a significantly attenuated the cycle arrest induced by lenvatinib, as well as the inhibitory effect of lenvatinib on ICC. Conclusion Our work first found that lenvatinib exerted an excellent antitumor effect on ICC, mainly via inducing Gadd45a-mediated cell cycle arrest. Our work provides evidence and a rationale for the future use of lenvatinib in the treatment of ICC.

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PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutant Endometrial Cancers

Cited by 37 publications

References 47 publications

Bcl‐2 inhibitors enhance FGFR inhibitor‐induced mitochondrial‐dependent cell death in FGFR2‐mutant endometrial cancer

Bcl‐2 inhibitors enhance FGFR inhibitor‐induced mitochondrial‐dependent cell death in FGFR2‐mutant endometrial cancer

Critical role of HOX transcript antisense intergenic RNA (HOTAIR) in gliomas

Lenvatinib inhibits intrahepatic cholangiocarcinoma via Gadd45a-mediated cell cycle arrest

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