American Association for Cancer Research
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Figure S4 from CDKN2A/p16 Deletion in Head and Neck Cancer Cells Is Associated with CDK2 Activation, Replication Stress, and Vulnerability to CHK1 Inhibition

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posted on 2023-03-31, 02:09 authored by 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

This file contains data showing relationship between cdk2 activity and Chk1 inhibition in hypersensitive UMSCC1-mVenus and least sensitive HN31-mVenus cells. This file is linked to main figure 5.

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Eli Lilly

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NIDCR

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ARTICLE 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. Cancer Res; 78(3); 781–97. ©2017 AACR.

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    Cancer Research

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    Keywords

    Cell CycleCDKs and CDK inhibitorsCell cycle checkpointsControl of cell cycle progressionDrug MechanismsCell cycle mechanisms of anticancer drug actionHead, Neck & Oral Cancers

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