CDKN2A/p16 deletion in head and neck cancer cells is associated with cdk2 activation, replication stress, and vulnerability to CHK1 inhibition

Mayur A. Gadhikar, Jiexin Zhang, Li Shen, Xiayu Rao, Jing Wang, Mei Zhao, Nene N. Kalu, Faye M. Johnson, Lauren A. Byers, John Heymach, Walter N. Hittelman, Durga Udayakumar, Raj K. Pandita, Tej K. Pandita, Curtis R. Pickering, Abena B. Redwood, Helen Piwnica-Worms, Katharina Schlacher, Mitchell J. Frederick, Jeffrey N. Myers

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Checkpoint kinase inhibitors (CHKi) exhibit striking single-agent activity in certain tumors, but the mechanisms accounting for hypersensitivity are poorly understood. We screened a panel of 49 established human head and neck squamous cell carcinoma (HNSCC) cell lines and report that nearly 20% are hypersensitive to CHKi monotherapy. Hypersensitive cells underwent early S-phase arrest at drug doses sufficient to inhibit greater than 90% of CHK1 activity. Reduced rate of DNA replication fork progression and chromosomal shattering were also observed, suggesting replication stress as a root causative factor in CHKi hypersensitivity. To explore genomic underpinnings of CHKi hypersensitivity, comparative genomic analysis was performed between hypersensitive cells and cells categorized as least sensitive because they showed drug IC50 value greater than the cell panel median and lacked early S-phase arrest. Novel association between CDKN2A/p16 copy number loss, CDK2 activation, replication stress, and hypersensitivity of HNSCC cells to CHKi monotherapy was found. Restoring p16 in cell lines harboring CDKN2A/p16 genomic deletions alleviated CDK2 activation and replication stress, attenuating CHKi hypersensitivity. Taken together, our results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from CHKi therapy. Significance: These results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from therapy with CHK inhibitors.

Original languageEnglish (US)
Pages (from-to)781-797
Number of pages17
JournalCancer research
Volume78
Issue number3
DOIs
StatePublished - Feb 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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