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Updated: Jun 6, 2026
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
Response of experimental malignant melanoma models to the pan-Aurora kinase inhibitor VE-465
Christine Pirker1, Daniela Lötsch, Sabine Spiegl-Kreinecker
1Institute of Cancer Research, Clinics for Medicine I, Medical University Vienna, Vienna, Austria.
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.
Insights
Aurora A kinase is overexpressed in melanoma and targeting it with inhibitors like VE-465 prevents colony formation. This suggests Aurora A is a promising target for new melanoma therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Aurora kinases are crucial for cell division and are implicated in cancer.
- Genomic instability, including gains at chromosome 20q, is common in cutaneous melanoma (CMM).
- The Aurora A gene locus is frequently amplified in CMM, leading to overexpression.
Purpose of the Study:
- To investigate the role of Aurora A kinase in CMM.
- To evaluate the efficacy of Aurora kinase inhibitors in CMM models.
- To explore the mechanisms of action and potential therapeutic strategies targeting Aurora A in melanoma.
Main Methods:
- Genomic analysis (classical and array CGH) of 51 CMM models.
- Overexpression analysis of Aurora A in CMM cell cultures.
- Long-term (7-10 days) and short-term (up to 72h) treatment with pan-Aurora kinase inhibitor VE-465.
- Assessment of cell cycle arrest, DNA synthesis, apoptosis, and p53/p21 activation.
- Use of Aurora B-specific inhibitor ZM447439 and Aurora A siRNA.
- Combination experiments with chemotherapeutic agents.
Main Results:
- Frequent gains at chromosome 20q, including the Aurora A locus, were observed in 65% of CMM models.
- The majority of CMM cell cultures overexpressed Aurora A, with detectable levels even in G1/S phase arrested cells.
- Long-term treatment with VE-465 completely inhibited colony formation in all CMM models at low concentrations (10-100 nm).
- VE-465 induced cell cycle arrest and DNA synthesis blockade dependent on p53/p21 activation, while unresponsiveness led to endoreduplication.
- Apoptosis induction by VE-465 and Aurora A siRNA was independent of p53/p21 status and DNA synthesis blockade.
- VE-465's apoptosis-inducing effect was predominantly due to Aurora A inhibition, as Aurora B inhibition was less effective.
- VE-465 showed additive to synergistic effects when combined with chemotherapeutic agents.
Conclusions:
- Aurora A kinase is frequently overexpressed in CMM due to genomic amplifications.
- Targeting Aurora A kinase with inhibitors like VE-465 is a promising strategy for melanoma therapy.
- VE-465 demonstrates potent anti-proliferative and apoptosis-inducing effects in CMM models, with potential for synergistic combinations.
