High-throughput screening identifies Aurora kinase B as a critical therapeutic target for Merkel cell carcinoma

作者：Tara Gelb, Khalid A. Garman, Daniel J. Urban, Amy Coxon, Berkley E. Gryder, Natasha T. Hill, Lingling Miao, Tobie D. Lee, Olivia W. Lee, Sirisha Chakka, John Braisted, Jordan E Jarvis, Rachael Glavin, Trisha Soosay Raj, Ying Xiao, Simone Difilippantonio, Amy Q. Wang, Min Shen, Ken Cheng, Madhu Lal-Nag, Matthew D. Hall, Isaac Brownell · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-56504-7 · 被引用次数：5 · 研究领域：Polyomavirus and related diseases、Bacteriophages and microbial interactions、Plant Virus Research Studies

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. Most MCCs contain Merkel cell polyomavirus (virus-positive MCC; VP-MCC), and the remaining are virus-negative (VN-MCC). Immune checkpoint inhibitors are the first-line treatment for metastatic MCC, but durable responses are achieved in less than 50% of patients. To identify new treatments, we screen ~4,000 compounds for their ability to reduce MCC viability and demonstrate that VP-MCC and VN-MCC exhibit distinct response profiles. Aurora kinase inhibitors selectively reduce VP-MCC viability, with RNAi screening independently identifying AURKB as an essential gene for MCC survival, especially in VP-MCC. AZD2811, a selective AURKB inhibitor, induces mitotic dysregulation and apoptosis in MCC cells, with greater efficacy in VP-MCC. In mice, AZD2811 nanoparticles inhibit tumor growth and increase survival in both VP-MCC and VN-MCC xenograft models. Overall, our unbiased screens identify AURKB as a promising therapeutic target and AZD2811NP as a potential treatment for MCC.