The Aurora Kinase Inhibitor CCT137690 Downregulates MYCN and SensitizesMYCN-Amplified NeuroblastomaIn Vivo

Abstract

Aurora kinases regulate key stages of mitosis including centrosome maturation, spindle assembly, chromosome segregation, and cytokinesis. Aurora A and B kinase overexpression has also been associated with various human cancers, and as such, they have been extensively studied as novel antimitotic drug targets. Here, we characterize the Aurora kinase inhibitor CCT137690, a highly selective, orally bioavailable imidazo [4,5-b]pyridine derivative that inhibits Aurora A and B kinases with low nanomolar IC 50 values in both biochemical and cellular assays and exhibits antiproliferative activity against a wide range of human solid tumor cell lines. CCT137690 efficiently inhibits histone H3 and transforming acidic coiled-coil 3 phosphorylation (Aurora B and Aurora A substrates, respectively) in HCT116 and HeLa cells. Continuous exposure of tumor cells to the inhibitor causes multipolar spindle formation, chromosome misalignment, polyploidy, and apoptosis. This is accompanied by p53/p21/BAX induction, thymidine kinase 1 downregulation, and PARP cleavage. Furthermore, CCT137690 treatment of MYCN-amplified neuroblastoma cell lines inhibits cell proliferation and decreases MYCN protein expression. Importantly, in a transgenic mouse model of neuroblastoma that overexpresses MYCN protein and is predisposed to spontaneous neuroblastoma formation, this compound significantly inhibits tumor growth. The potent preclinical activity of CCT137690 suggests that this inhibitor may benefit patients with MYCN-amplified neuroblastoma. Mol Cancer Ther; 10(11); 2115-23. Ó2011 AACR.

Targeting GD2 ganglioside and aurora A kinase as a dual strategy leading to cell death in cultures of human neuroblastoma cells

“…Aurora A and B kinases are highly expressed, and AURKA gene loci is amplified in multiple human tumors relative to normal tissue [10]. Therefore, aurora kinases have been extensively studied as novel antimitotic drug targets [11,12], and several specific inhibitors have been developed, and are evaluated in preclinical models, as well as in different phases of clinical trials [13,14]. The effects of aurora A kinase inhibition are multiple, and include abnormal spindle pole formation, proliferation reduction (with G2-M arrest), and polyploidy, followed by apoptosis induction [15].…”

High proliferation index, as determined by immunohistochemical expression of Aurora kinase B and geminin, indicates poor prognosis in neuroblastomas

“…This is not surprising because others have reported association of over-expression of MYCN protein with upregulation of cell cycle proliferation markers such as AURKA and AURKB [23,24]. In addition, treatment of MYCN-amplified neuroblastoma cell lines with CCT137690, a dual inhibitor of Aurora kinase A and B activity, decreases MYCN protein expression and inhibits cell proliferation [11]. CCT137690 also significantly inhibits NB tumor growth in transgenic mice that over-express MYCN protein, which predisposes them to spontaneous NB formation [11].…”

“…In addition, treatment of MYCN-amplified neuroblastoma cell lines with CCT137690, a dual inhibitor of Aurora kinase A and B activity, decreases MYCN protein expression and inhibits cell proliferation [11]. CCT137690 also significantly inhibits NB tumor growth in transgenic mice that over-express MYCN protein, which predisposes them to spontaneous NB formation [11].…”

“…Other key components of S-G2-M phases of the cell cycle include Aurora kinase B (AURKB) and geminin (GMNN). Pre-clinical data have shown that inhibition of AURKB activity significantly decreases NB cell viability in vitro [10,11] and inhibits tumor growth in xenograft models [11]. GMNN activity is inhibited by the natural compound apigenin in human pancreatic cancer cell lines at both transcriptional and protein levels [12].…”

A Phase I Trial of AT9283 (a Selective Inhibitor of Aurora Kinases) in Children and Adolescents with Solid Tumors: A Cancer Research UK Study

“…They comprise Aurora A (involved in centrosome separation and maturation and bipolar spindle assembly) and Aurora B ("chromosome passenger protein"; mediating chromosome segregation and cytokinesis and phosphorylation of a number of targets, including histone H3), which have been shown to act as oncogenic drivers in a number of human cancers (2,3). The preclinical rationale supporting the clinical development of Aurora kinase inhibitors in children with solid tumors is particularly strong because: (i) the target is dysregulated in a number of high-risk malignancies such as neuroblastoma, medulloblastoma, central nervous system primitive neuroectodermal tumor (CNS-PNET), and malignant glioma; (ii) there is a mechanistic justification of its indispensable role in MYC/MYCN-driven cancers such as neuroblastoma; (iii) there are in vitro and in vivo efficacy data, including in genetically engineered murine models; (iv) there are several drugs under development; and (v) pharmacodynamic (PD) biomarkers are available to demonstrate target inhibition in patients (4)(5)(6)(7)(8)(9)(10). AT9283 is a multitargeted inhibitor against Aurora A and B, JAK2 and ABL kinases, and has been tested in phase I/II trials in adults with solid and hematologic cancers (11)(12)(13)(14)(15).…”