Background: Most patients with advanced lung cancer will receive platinum-based therapy during their treatment course despite limited clinical benefits. Thus, strategies to improve platinum-based therapy continue to be needed. Through a functional genetic screen, we have identified Aurora kinase A as a potentially actionable candidate that can modulate the activity of platinum compounds. Aurora A is a serine/threonine kinase and a key regulator of the mitotic process. Through its mitotic and non-mitotic roles, the aberrant activation of Aurora A can lead to oncogenic transformation and has emerged as a promising therapeutic target in cancer.
METHODS: High-throughput RNAi screen was used to identify potential candidates for cisplatin resistance. Cell proliferation/viability was determined by MTS assays and colony formation assays. Immunohistochemistry was performed to determine the overexpression of Aurora A in specimens from lung cancer patients. Western blot was used to explore the cell signaling mechanisms in cisplatin, radiation, and/or MLN8237 (alisertib) treated NSCLC cell lines. β-Galactosidase staining was performed to determine the senescence following cisplatin and/or MLN8237 treatment in NSCLC cell lines.
RESULTS: Aurora Kinase A is widely expressed in lung cancer specimens. The expression of Aurora A is upregulated following treatment with Cisplatin in NSCLC cells, such as PC9, A549, H1703, and H460. Inhibition of Aurora A activity with either siRNA-mediated knockdown or pharmacological blockade (MLN8237) significantly improved sensitivities to cisplatin and ionizing radiation, both of which cause DNA damage and cell death. On the other hand, inhibition of Aurora A activity by itself was associated with reduced cell proliferation and survival of NSCLC cell lines. Moreover, co-administration with Cisplatin and AURKA siRNA resulted in sustained DNA double strand breaks and more pronounced apoptosis. The combination of AURKA inhibitor (MLN8237) with Cisplatin similarly led to enhanced DNA damage. Similar effects were observed with radiation concomitant with inhibition of Aurora A. Furthermore, MLN8237 induced marked apoptosis in the p53 mutant cell line, PC9, whereas more senescence was noted in p53 wild type A549 cells.
CONCLUSIONS: Our study indicates a significant role for Aurora Kinase A as a common modulator of p53-dependent resistance in the context of DNA-damaging platinum and radiation therapy. Aurora A inhibition can potentially improve the efficacy of these common treatment modalities in lung cancer management.
Citation Format: Huijie Liu, Dongwei Zhang, Alain Borczuk, Vincent Chau, Roman Perez-Soler, Balazs Halmos, Haiying Cheng. Blockade of Aurora kinase A synergizes with platinum and radiation in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1217. doi:10.1158/1538-7445.AM2017-1217