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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月12日

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  • 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,
  • Isaac Brownell

摘要

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.