Response of experimental malignant melanoma models to the pan‐Aurora kinase inhibitor VE‐465

Abstract

Aurora kinases represent promising novel cancer therapy targets. Genomic analyses of human cutaneous melanoma (CMM) models (N = 51, low passage) by classical and/or array CGH revealed frequent gains at chromosome 20q (65%, amplifications in 45%) repeatedly including the Aurora A gene locus. Accordingly, the majority of CMM cell cultures overexpressed Aurora A when compared to proliferating non-malignant cells. Moreover, CMM cells even when arrested in G1/S cell cycle phase contained readily detectable levels of Aurora A indicating incomplete degradation during mitosis. Already at low concentrations (10-100 nm), long-term (7-10 days) application of the pan-Aurora kinase inhibitor VE-465 completely prevented colony formation in all CMM models tested. In contrast, blockade of cell survival/proliferation and DNA synthesis as well as the induction of apoptosis by VE-465 distinctly differed in short-term experiments (up to 72 h exposure). Both cell cycle arrest and DNA synthesis blockade depended on the level of VE-465-mediated p53/p21 activation while p53/p21 unresponsiveness led to repetitive endoreduplication (>8n DNA content). In contrast, apoptosis induction by VE-465 and Aurora A siRNA did not correlate with p53/p21 responsiveness and DNA synthesis blockade. Moreover, application of the Aurora B-specific inhibitor ZM447439 and siRNA was less efficient to induce CMM cell death proofing that apoptosis induction by VE-465 depended predominantly on Aurora A targeting. In combination experiments with chemotherapeutic agents, VE-465 acted additive to antagonistic when applied concomitantly but in several cases even synergistic when applied consecutively. In summary, we suggest that the Aurora A kinase might represent a promising target of well-designed novel antimelanoma strategies.

Aurora B Is Regulated by the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (MAPK/ERK) Signaling Pathway and Is a Valuable Potential Target in Melanoma Cells

“…Cell death by mitotic catastrophe is evidenced by polyploidization, caspase-2 activation, and detection of dead cells. Previous works with pan-Aurora inhibitors in melanoma cells (5,28) and in other tumor types (10,20) reported similar effects. The progressive disappearance of both Cyclin B1 and CDK1 after Aurora B suppression is consistent with cells that exit mitosis without completion of cytokinesis and with cells that enter a new round of cell division at a higher DNA content.…”

“…Given their function in the control of the G 2 /M phase, the expression of the chromosomal passenger protein complex proteins is controlled in a cell cycle-dependent manner. However, in-creased expression of some of these components such as Aurora B and Survivin has been observed in a spectrum of cancers, including melanoma (5,6), and predicts early tumor recurrence and poor prognosis (7,8).…”

“…Aurora B belongs to the mammalian Aurora Kinase family Aurora A (AURKA), Aurora B (AURKB), and Aurora C (AURKC). Inhibitors of Aurora kinases, ZM447439, PHA-680, hesperadin, PF-03814735, SNS-314, VE-465, and MK0457/VX-680, have shown promising anti-tumor effects in several cell types (9,10), including melanoma cells (5,6). Recently, AZD1152, a highly potent and specific aurora kinase inhibitor with 1000-fold selectivity for Aurora B over Aurora A kinase activity, has been developed (11).…”

“…Recently, AZD1152, a highly potent and specific aurora kinase inhibitor with 1000-fold selectivity for Aurora B over Aurora A kinase activity, has been developed (11). AZD1152 is a prodrug that is metabolized in the serum to its active form AZD1152-hydroxyquinazoline pyrazol anilide (HQPA), 5 an ATP binding pocket competitor. Preclinical studies have shown the antineoplasic properties of AZD1152 in acute myelogenous leukemia, multiple myeloma, colorectal and breast cancer, yet the effect of AZD1152 remains to be explored in melanoma cells.…”

The Novel ATP-Competitive MEK/Aurora Kinase Inhibitor BI-847325 Overcomes Acquired BRAF Inhibitor Resistance through Suppression of Mcl-1 and MEK Expression

“…Of these, overexpression of Aurora A in NIH-3T3 cells is known to enhanced colony formation and solid tumor formation, as well as being implicated in the emergence of centrosome abnormalities and aneuploidy in breast cancer (45, 46). Previous studies have reported that overexpression of Aurora kinase B contributes to melanoma progression by causing genomic instability and aneuploidy (15, 47). Other work has implicated Aurora kinase in the escape from vemurafenib therapy, with 2 BRAF inhibitor resistant cell lines showing sensitivity to the Aurora kinase B inhibitor AZD1152 (15).…”