Targeting Aurora kinase-A downregulates cell proliferation and angiogenesis in neuroblastoma.

Aurora kinase A (AURKA) overexpression is associated with poor prognosis in neuroblastoma and has been described to upregulate VEGF in gastric cancer cells. However, the exact role of AURKA in the regulation of neuroblastoma tumorigenesis remains unknown. We hypothesize that AURKA-mediated stabilization of N-Myc may affect VEGF expression and angiogenesis in neuroblastoma. Therefore, we sought to determine whether inhibition of AURKA modulates neuroblastoma angiogenesis. Cell viability and anchorage-independent growth were determined after silencing AURKA or after treatment with MLN8237, AURKA inhibitor. Immunofluorescence was used to determine N-Myc localization. Human umbilical vein endothelial cells (HUVECs) were used to assess angiogenesis in vitro. Real time-PCR and ELISA were performed to determine VEGF transcription and secretion, respectively. Knockdown of AURKA significantly reduced cell proliferation and inhibited anchorage-independent growth. It also decreased N-Myc protein levels and nuclear localization. AURKA inhibition also decreased HUVECs tubule formation along with VEGF transcription and secretion. Similarly, MLN8237 treatment decreased neuroblastoma tumorigenicity in vitro. Our findings demonstrate that AURKA plays a critical role in neuroblastoma angiogenesis. AURKA regulates nuclear translocation of N-Myc in neuroblastoma cells, thus potentially affecting cell proliferation, anchorage-independent cell growth, and angiogenesis. Targeting AURKA might provide a novel therapeutic strategy in treating aggressive neuroblastomas.

Romain C ，Paul P ，Kim KW ，Lee S ，Qiao J ，Chung DH ... -  《-》

PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc.

Boi D ，Souvalidou F ，Capelli D ，Polverino F ，Marini G ，Montanari R ，Pochetti G ，Tramonti A ，Contestabile R ，Trisciuoglio D ，Carpinelli P ，Ascanelli C ，Lindon C ，De Leo A ，Saviano M ，Di Santo R ，Costi R ，Guarguaglini G ，Paiardini A ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

c-Myc Is a Major Determinant for Antitumor Activity of Aurora A Kinase Inhibitor MLN8237 in Thyroid Cancer.

Li Y ，Li X ，Pu J ，Yang Q ，Guan H ，Ji M ，Shi B ，Chen M ，Hou P ... -  《-》

Dual BRD4 and AURKA Inhibition Is Synergistic against MYCN-Amplified and Nonamplified Neuroblastoma.

A majority of cases of high-risk neuroblastoma, an embryonal childhood cancer, are driven by MYC or MYCN-driven oncogenic signaling. While considered to be directly "undruggable" therapeutically, MYC and MYCN can be repressed transcriptionally by inhibition of Bromodomain-containing protein 4 (BRD4) or destabilized posttranslationally by inhibition of Aurora Kinase A (AURKA). Preclinical and early-phase clinical studies of BRD4 and AURKA inhibitors, however, show limited efficacy against neuroblastoma when used alone. We report our studies on the concomitant use of the BRD4 inhibitor I-BET151 and AURKA inhibitor alisertib. We show that, in vitro, the drugs act synergistically to inhibit viability in four models of high-risk neuroblastoma. We demonstrate that this synergy is driven, in part, by the ability of I-BET151 to mitigate reflexive upregulation of AURKA, MYC, and MYCN in response to AURKA inhibition. We then demonstrate that I-BET151 and alisertib are effective in prolonging survival in four xenograft neuroblastoma models in vivo, and this efficacy is augmented by the addition of the antitubule chemotherapeutic vincristine. These data suggest that epigenetic and posttranslational inhibition of MYC/MYCN-driven pathways may have significant clinical efficacy against neuroblastoma.

Felgenhauer J ，Tomino L ，Selich-Anderson J ，Bopp E ，Shah N ... -  《NEOPLASIA》

Polymer Nanovesicle-Mediated Delivery of MLN8237 Preferentially Inhibits Aurora Kinase A To Target RalA and Anchorage-Independent Growth in Breast Cancer Cells.

Inchanalkar S ，Deshpande NU ，Kasherwal V ，Jayakannan M ，Balasubramanian N ... -  《-》