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Research Letter
February 16, 2017

Strategies for Targeted Therapy in Head and Neck Squamous Cell Carcinoma Using WEE1 Inhibitor AZD1775

Author Affiliations
  • 1Department of Otolaryngology–Head and Neck Surgery, University of Washington, Seattle
  • 2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 3Department of Pathology, University of Washington, Seattle
JAMA Otolaryngol Head Neck Surg. Published online February 16, 2017. doi:10.1001/jamaoto.2016.4563

We previously reported on the use of the high-throughput RNA interference kinome screen to identify genes required for the survival of p53 mutant head and neck squamous cell carcinoma (HNSCC) cells but not that of normal cells.1 We identified p53 synthetic lethal interactions with several G2/M checkpoint regulators, including WEE1 and CHK1, and found HNSCC killing by the WEE1 inhibitor AZD1775.1 During DNA damage, WEE1 initiates G2/M arrest via inhibition of cyclin-dependent kinase 1 to prevent mitosis and allow DNA repair. WEE1 also stabilizes DNA replication forks during S phase via a cyclin-dependent kinase 2 mechanism. Thus, WEE1 inhibition likely leads to unrestrained or premature mitosis and replication stress.2,3

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