Aurora kinase A is a possible target of OSU-03012 to destabilize MYC family proteins

Silva, Andres; Wang, Jennie; Lomahan, Sarah; Tran, Tuan Anh; Grenlin, Laura; Suganami, Akiko; Tsutsumi, Yutaka; Ikegaki, Naohiko

doi:10.3892/or.2014.3325

Cited by 13 publications

(10 citation statements)

References 22 publications

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“…We confirmed the on‐target activity of I‐BET151 against BRD4, demonstrating the transcriptional repression of multiple canonical BRD4 targets previously validated in different cancers . We also confirmed AURKA kinase inhibition by alisertib and concomitant MYC repression, consistent with prior studies . Our work does not preclude other biological impacts of alisertib and I‐BET151 on ES biology; in fact, we do confirm that BRD4 inhibition does impair EWS‐FLI1‐mediated transcriptional activation as shown by I‐BET151's repression of NR0B1, consistent with recent data .…”

Section: Discussionsupporting

confidence: 89%

Combinatorial BRD4 and AURKA inhibition is synergistic against preclinical models of Ewing sarcoma

et al. 2019

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Background: Ewing sarcoma (ES), a bone cancer affecting children, adolescents, and young adults, is driven by the EWS-FLI1 fusion protein in the majority of cases, but the mechanisms of tumorigenesis are still being elucidated. Consequentially, therapeutic advances have been limited in the last 25 years. Two therapeutic targets have been recently examined. Aurora kinase A (AURKA) promotes cell cycling and posttranslational stabilization of the oncoprotein MYC, while bromodomain-containing protein 4 (BRD4) promotes gene expression epigenetically. Studies of AURKA and BRD4 inhibitors showed some impairment of tumorigenesis in ES preclinical models, but this efficacy was limited in single-agent use. AURKA and BRD4 activate common oncogenic pathways through different mechanisms, so we hypothesized dual inhibition would be synergistic against tumorigenesis. Aims: (a) Define the synergistic antineoplastic effects of BRD4 inhibitor I-BET151 and AURKA inhibitor alisertib against ES cell lines in vitro. (b) Confirm the mechanism of activity of each agent in these cell line models. (c) Define the efficacy of I-BET 151 and alisertib alone and in combinations with each other, and with the chemotherapeutic drug vincristine against ES tumor xenografts in vivo. Methods and results: I-BET151 and alisertib synergistically inhibit viability in ES cell lines SK-ES, TC71, and ES2 in vitro. Alisertib alone upregulates transcriptional expression of its targets, but combined use of I-BET151 mitigates that upregulation, likely contributing to the drug synergy and downregulating RNA and protein expression of key oncogenic pathways as shown by RT-qPCR and western blot. Alisertib and I-BET151 significantly prolong survival in three ES xenograft models in vivo, and this efficacy is augmented by the addition of vincristine. Conclusion: Dual targeting of oncogenic drivers in ES epigenetically and posttranslationally, specifically by use of BRD4 and AURKA inhibitors, may have significant clinical efficacy in ES alone and/or in combination with current chemotherapy regimens.

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Section: Discussionsupporting

confidence: 89%

Combinatorial BRD4 and AURKA inhibition is synergistic against preclinical models of Ewing sarcoma

et al. 2019

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“…Despite intense investigations, no effective strategies exist to target C-MYC. C-MYC upregulates the expression of AURKA [41], while AURKA activity protects C-MYC from degradation [42]. AURKA signals through C-MYC to induce telomerase, supporting tumor immortalization [43].…”

Section: Discussionmentioning

confidence: 99%

Combined inhibition of Aurora A and p21-activated kinase 1 as a new treatment strategy in breast cancer

Korobeynikov

Borakove

Feng

et al. 2019

Breast Cancer Res Treat

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Purpose The serine-threonine kinases Aurora A (AURKA) and p21-activated kinase 1 (PAK1) are frequently overexpressed in breast tumors, with overexpression promoting aggressive breast cancer phenotypes and poor clinical outcomes. Besides the well-defined roles of these proteins in control of cell division, proliferation, and invasion, both kinases support MAPK kinase pathway activation and can contribute to endocrine resistance by phosphorylating estrogen receptor alpha (ERα). PAK1 directly phosphorylates AURKA and its functional partners, suggesting potential value of inhibiting both kinases activity in tumors overexpressing PAK1 and/or AURKA. Here, for the first time, we evaluated the effect of combining the AURKA inhibitor alisertib and the PAK inhibitor FRAX1036 in preclinical models of breast cancer. Methods Combination of alisertib and FRAX1036 was evaluated in a panel of 13 human breast tumor cell lines and BT474 xenograft model, with assessment of the cell cycle by FACS, and signaling changes by immunohistochemistry and Western blot. Additionally, we performed in silico analysis to identify markers of response to alisertib and FRAX1036. Results Pharmacological inhibition of AURKA and PAK1 synergistically decreased survival of multiple tumor cell lines, showing particular effectiveness in luminal and HER2-enriched models, and inhibited growth and ERα-driven signaling in a BT474 xenograft model. In silico analysis suggested cell lines with dependence on AURKA are most likely to be sensitive to PAK1 inhibition. Conclusion Dual targeting of AURKA and PAK1 may be a promising therapeutic strategy for treatment of breast cancer, with a particular effectiveness in luminal and HER2-enriched tumor subtypes. Electronic supplementary material The online version of this article (10.1007/s10549-019-05329-2) contains supplementary material, which is available to authorized users.

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“…We have previously shown that AURKA can regulate transcription of c-MYC through the activation of b-catenin (Dar et al, 2009). Recent studies have shown that inhibition of AURKA can regulate phosphorylation and stability of MYC, suggesting targeting AURKA-MYC axis by AURKA inhibitors as a novel potentially effective therapeutic approach (Dauch et al, 2016;Richards et al, 2016;Silva et al, 2014). We investigated whether eIF4E and its downstream effector, c-MYC, mediate the function of AURKA and CDDP resistance.…”

Section: Discussionmentioning

confidence: 99%

Cisplatin‐resistant cancer cells are sensitive to Aurora kinase A inhibition by alisertib

et al. 2017

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De novo and acquired resistance to platinum therapy such as cisplatin (CDDP) is a clinical challenge in gastric cancer treatment. Aberrant expression and activation of Aurora kinase A (AURKA) and eukaryotic translation initiation factor 4E (eIF4E) are detected in several cancer types. Herein, we investigated the role of AURKA in CDDP resistance in gastric cancer. Western blot analysis demonstrated overexpression of AURKA and phosphorylation of eIF4E in acquired and de novo CDDP-resistant gastric cancer models. Inhibition of AURKA with MLN8237 (alisertib) alone or in combination with CDDP significantly suppressed viability of CDDP-resistant cancer cells (p<0.01). Additionally, inhibition or knockdown of AURKA decreased protein expression of p-eIF4E (S209), HDM2, and c-MYC in CDDP-resistant cell models. This was associated with a significant decrease in cap-dependent translation levels (p<0.01). In vivo tumor xenografts data corroborated these results and confirmed that inhibition of AURKA was sufficient to overcome CDDP resistance in gastric cancer. Our data demonstrate that AURKA promotes acquired and de novo resistance to CDDP through regulation of p-eIF4E (S209), c-MYC, HDM2, and cap-dependent translation. Targeting AURKA could be an effective therapeutic approach to overcome CDDP resistance in refractory gastric cancer and possibly other cancer types.

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Aurora kinase A is a possible target of OSU-03012 to destabilize MYC family proteins

Cited by 13 publications

References 22 publications

Combinatorial BRD4 and AURKA inhibition is synergistic against preclinical models of Ewing sarcoma

Combinatorial BRD4 and AURKA inhibition is synergistic against preclinical models of Ewing sarcoma

Combined inhibition of Aurora A and p21-activated kinase 1 as a new treatment strategy in breast cancer

Cisplatin‐resistant cancer cells are sensitive to Aurora kinase A inhibition by alisertib

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