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Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma.

Publication ,  Journal Article
Chaudhary, R; Slebos, RJC; Song, F; McCleary-Sharpe, KP; Masannat, J; Tan, AC; Wang, X; Amaladas, N; Wu, W; Hall, GE; Conejo-Garcia, JR ...
Published in: Mol Carcinog
February 2021

Prognosis for patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) remains poor. Development of more effective and less toxic targeted therapies is necessary for HNSCC patients. Checkpoint kinase 1 (CHK1) plays a vital role in cell cycle regulation and is a promising therapeutic target in HNSCC. Prexasertib, a CHK1 inhibitor, induces DNA damage and cell death, however, its effect on the tumor immune microenvironment (TIME) is largely unknown. Therefore, we evaluated a short-term and long-term effects of prexasertib in HNSCC and its TIME. Prexasertib caused increased DNA damage and cell death in vitro and significant tumor regression and improved survival in vivo. The gene expression and multiplex immunohistochemistry (mIHC) analyses of the in vivo tumors demonstrated increased expression of genes that are related to T-cell activation and increased immune cell trafficking, and decreased expression of genes that related to immunosuppression. However, increased expression of genes related to immunosuppression emerged over time suggesting evasion of immune surveillances. These findings in gene expression analyses were confirmed using mIHC which showed differential modulation of TIME in the tumor margins and as well as cores over time. These results suggest that evasion of immune surveillance, at least in part, may contribute to the acquired resistance to prexasertib in HNSCC.

Duke Scholars

Published In

Mol Carcinog

DOI

EISSN

1098-2744

Publication Date

February 2021

Volume

60

Issue

2

Start / End Page

138 / 150

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Tumor Burden
  • Survival Analysis
  • Pyrazoles
  • Pyrazines
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mice, Inbred C57BL
  • Male
 

Citation

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Chaudhary, R., Slebos, R. J. C., Song, F., McCleary-Sharpe, K. P., Masannat, J., Tan, A. C., … Chung, C. H. (2021). Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma. Mol Carcinog, 60(2), 138–150. https://doi.org/10.1002/mc.23275
Chaudhary, Ritu, Robbert J. C. Slebos, Feifei Song, Keegan P. McCleary-Sharpe, Jude Masannat, Aik Choon Tan, Xuefeng Wang, et al. “Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma.Mol Carcinog 60, no. 2 (February 2021): 138–50. https://doi.org/10.1002/mc.23275.
Chaudhary R, Slebos RJC, Song F, McCleary-Sharpe KP, Masannat J, Tan AC, et al. Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma. Mol Carcinog. 2021 Feb;60(2):138–50.
Chaudhary, Ritu, et al. “Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma.Mol Carcinog, vol. 60, no. 2, Feb. 2021, pp. 138–50. Pubmed, doi:10.1002/mc.23275.
Chaudhary R, Slebos RJC, Song F, McCleary-Sharpe KP, Masannat J, Tan AC, Wang X, Amaladas N, Wu W, Hall GE, Conejo-Garcia JR, Hernandez-Prera JC, Chung CH. Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma. Mol Carcinog. 2021 Feb;60(2):138–150.

Published In

Mol Carcinog

DOI

EISSN

1098-2744

Publication Date

February 2021

Volume

60

Issue

2

Start / End Page

138 / 150

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Tumor Burden
  • Survival Analysis
  • Pyrazoles
  • Pyrazines
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mice, Inbred C57BL
  • Male