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

Tara Gelb, Khalid A. Garman, Daniel Urban, Amy Coxon, Berkley Gryder, Natasha T. Hill, Lingling Miao, Tobie Lee, Olivia Lee, Sirisha Chakka, John Braisted, Jordan E. Jarvis, Rachael Glavin, Trisha S. Raj, Ying Xiao, Simone Difilippantonio, Amy Q. Wang, Min Shen, Ken Chih-Chien Cheng, Madhu Lal-Nag, Matthew D. Hall and Isaac Brownell ()
Additional contact information
Tara Gelb: National Institutes of Health
Khalid A. Garman: National Institutes of Health
Daniel Urban: National Institutes of Health
Amy Coxon: National Institutes of Health
Berkley Gryder: National Institutes of Health
Natasha T. Hill: National Institutes of Health
Lingling Miao: National Institutes of Health
Tobie Lee: National Institutes of Health
Olivia Lee: National Institutes of Health
Sirisha Chakka: National Institutes of Health
John Braisted: National Institutes of Health
Jordan E. Jarvis: National Institutes of Health
Rachael Glavin: National Institutes of Health
Trisha S. Raj: National Institutes of Health
Ying Xiao: National Institutes of Health
Simone Difilippantonio: Frederick National Laboratory for Cancer Research
Amy Q. Wang: National Institutes of Health
Min Shen: National Institutes of Health
Ken Chih-Chien Cheng: National Institutes of Health
Madhu Lal-Nag: National Institutes of Health
Matthew D. Hall: National Institutes of Health
Isaac Brownell: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-56504-7

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