In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor

Yu, Yi; Hall, T.M.T.; Eathiraj, Sudharshan; Wick, Michael J.; Schwartz, Brian; Abbadessa, Giovanni

doi:10.1097/cad.0000000000000486

Cited by 23 publications

(20 citation statements)

References 45 publications

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“…For patients with advanced metastatic or recurrent endometrial cancer, treatment failure is still high due to the loss of opportunity for surgery. With the elucidation of molecular mechanisms in endometrial cancer, an increasing number of molecular targeted drugs are being tested for clinical application, and some have shown beneficial effects [ 3 , 4 ]. Therefore, the potential mechanisms in the development of endometrial cancer, especially those involved in tumour metastasis, have become the basis for the development of molecular targeted therapy for endometrial cancer, which is essential for the treatment of this type of cancer.…”

Section: Introductionmentioning

confidence: 99%

miR-302a-5p/367-3p-HMGA2 axis regulates malignant processes during endometrial cancer development

Kong

et al. 2018

J Exp Clin Cancer Res

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BackgroundMetastasis is one of the main reasons for treatment failure in endometrial cancer. Notably, high mobility group AT-hook 2 (HMGA2) has been recognized as a driving factor of tumour metastasis. microRNAs (miRNAs) are powerful posttranscriptional regulators of HMGA2.MethodsThe binding sites of miR-302a-5p and miR-367-3p on HMGA2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. The expression levels of miR-302a-5p and miR-367-3p were detected using quantitative real-time PCR and in situ hybridization. Western blotting and immunohistochemistry were used to detect the levels of HMGA2 and epithelial-mesenchymal transition pathway-related proteins. Co-immunoprecipitation was used to detect protein interactions. The roles of miR-302a-5p and miR-367-3p in the regulation of HMGA2 during the progression of endometrial cancer were investigated using both in vitro and in vivo assays.ResultsIn the present study, high HMGA2 expression was correlated with poor clinical outcomes in endometrial cancer. The binding sites of miRNAs on HMGA2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. In the endometrial cancer cell lines Ishikawa and HEC-1A, the overexpression of miR-302a-5p/367-3p significantly inhibited the expression of HMGA2 mRNA. In endometrial cancer tissues, we showed that miR-302a-5p and miR-367-3p were significantly downregulated and thus inversely correlated with HMGA2. The miR-302a-5p and miR-367-3p expression levels were closely correlated with FIGO stage and lymph node metastasis. High expression of miR-302a-5p/367-3p was correlated with high survival rates in endometrial cancer. In addition, miR-302a-5p/367-3p suppressed the malignant behaviour of endometrial carcinoma cells via the inhibition of HMGA2 expression.ConclusionOur findings indicate that miR-302a-5p/367-3p-mediated expression of HMGA2 regulates the malignant behaviour of endometrial carcinoma cells, which suggests that the miR-302a-5p/367-3p-HMGA2 axis may be a predictive biomarker of endometrial cancer metastasis and patient survival and a potential therapeutic target in metastatic endometrial cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0686-6) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

miR-302a-5p/367-3p-HMGA2 axis regulates malignant processes during endometrial cancer development

Kong

et al. 2018

J Exp Clin Cancer Res

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“…Studies have shown that cancers with high expression of FGFR mRNA and protein are more likely to respond to FGFR inhibitors (Goke et al, 2015b;Pearson et al, 2016;Weiss et al, 2010). In addition, we and others have shown that in preclinical models where FGFR inhibition does not block PI3K pathway activation, the combination of FGFR and AKT/PI3K/ mTOR inhibition resulted in increased cell death (Fumarola et al, 2017;Packer et al, 2017;Yu et al, 2017). However, despite preclinical efficacy, dual FGFR/PI3K inhibition is unlikely to be evaluated in clinical trials due to its combined toxicity (Hyman et al, 2016).…”

Section: Discussionmentioning

confidence: 98%

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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“…Deregulation of this pathway causes amplification and mutation of genes encoding PI3K and AKT. Targeting the PI3K/AKT pathway and its downstream targets like FOXO1 and GSK3 appears to be an attractive approach to treat cancers that are known to have aberrant AKT activation [49]. High levels of constitutive AKT has been associated with a short survival rate in cancer patients [50,51].…”

Section: Discussionmentioning

confidence: 99%

Greensporone A, a Fungal Secondary Metabolite Suppressed Constitutively Activated AKT via ROS Generation and Induced Apoptosis in Leukemic Cell Lines

et al. 2019

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Greensporone A is a fungal secondary metabolite that has exhibited potential in vitro for anti-proliferative activity in vitro. We studied the anticancer activity of greensporone A in a panel of leukemic cell lines. Greensporone A-mediated inhibition of proliferation is found to be associated with the induction of apoptotic cell death. Greensporone A treatment of leukemic cells causes inactivation of constitutively activated AKT and its downstream targets, including members GSK3 and FOXO1, and causes downregulation of antiapoptotic genes such as Inhibitor of Apoptosis (IAPs) and Bcl-2. Furthermore, Bax, a proapoptotic member of the Bcl-2 family, was found to be upregulated in leukemic cell lines treated with greensporone A. Interestingly, gene silencing of AKT using AKT specific siRNA suppressed the expression of Bcl-2 with enhanced expression of Bax. Greensporone A-mediated increase in Bax/Bcl-2 ratio causes permeabilization of the mitochondrial membrane leading to the accumulation of cytochrome c in the cytoplasm. Greensporone A-induced cytochrome c accumulation causes the activation of caspase cascade and cleavage of its effector, poly(ADP-ribose) polymerase (PARP), leading to apoptosis. Greensporone A-mediated apoptosis in leukemic cells occurs through the generation of reactive oxygen species (ROS) due to depletion of glutathione (GSH) levels. Finally, greensporone A potentiated the anticancer activity of imatinib in leukemic cells. In summary, our study showed that greensporone A suppressed the growth of leukemic cells via induction of apoptotic cell death. The apoptotic cell death occurs by inhibition of AKT signaling and activation of the intrinsic apoptotic/caspase pathways. These results raise the possibility that greensporone A could be developed as a therapeutic agent for the treatment of leukemia and other hematological malignancies.

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In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor

Abstract: Supplemental Digital Content is available in the text.

Cited by 23 publications

References 45 publications

miR-302a-5p/367-3p-HMGA2 axis regulates malignant processes during endometrial cancer development

miR-302a-5p/367-3p-HMGA2 axis regulates malignant processes during endometrial cancer development

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

Greensporone A, a Fungal Secondary Metabolite Suppressed Constitutively Activated AKT via ROS Generation and Induced Apoptosis in Leukemic Cell Lines

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