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MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma

Abstract

Radiation therapy (RT) is a cornerstone of treatment in the management of head and neck squamous cell carcinomas (HNSCC), yet treatment failure and disease recurrence are common. The p38/MK2 pathway is activated in response to cellular stressors, including radiation, and promotes tumor inflammation in a variety of cancers. We investigated MK2 pathway activation in HNSCC and the interaction of MK2 and RT in vitro and in vivo. We used a combination of an oropharyngeal SCC tissue microarray, HNSCC cell lines, and patient-derived xenograft (PDX) tumor models to study the effect of RT on MK2 pathway activation and to determine how inhibition of MK2 by pharmacologic (PF-3644022) and genetic (siRNA) methods impacts tumor growth. We show that high phosphorylated MK2 (p-MK2) levels are associated with worsened disease-specific survival in p16-negative HNSCC patients. RT increased p-MK2 in both p16-positive, HPV-positive and p16-negative, HPV-negative HNSCC cell lines. Pharmacologic inhibition or gene silencing of MK2 in vitro abrogated RT-induced increases in p-MK2; inflammatory cytokine expression and expression of the downstream MK2 target, heat shock protein 27 (HSP27); and markers of epithelial-to-mesenchymal transition. Mouse PDX models treated with a combination of RT and MK2 inhibitor experienced decreased tumor growth and increased survival. Our results suggest that MK2 is a potential prognostic biomarker for head and neck cancer and that MK2 pathway activation can mediate radiation resistance in HNSCC.

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Acknowledgements

Work supported in part by RSNA Foundation Research Scholar Grant, ACS-IRG (IRG-14-187-19), Dedicated Health Research Fund from the University of New Mexico School of Medicine (UNM RAC 2018), STI CRC (U19 AI 113187), and the NIH P30 Grant NCI P30CA118100. The research in this paper was supported by the Human Tissue Repository and Tissue Analysis Shared Resource, funded by the Department of Pathology and The University of New Mexico Comprehensive Cancer Center and NCI P30CA118100. Many of the images in this paper were generated in the University of New Mexico Cancer Center Fluorescence Microscopy Shared Resource with current funding from NCI 2P30 CA118100. Initial support with PDX generation was performed with the assistance from the University of New Mexico Cancer Center Animal Shared Resource funded by NCI 2P30 CA118100. We also wish to acknowledge UNM Cancer Center Biostatistics Core Facility for their statistical assistance.

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Berggren, K.L., Restrepo Cruz, S., Hixon, M.D. et al. MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma. Oncogene 38, 7329–7341 (2019). https://doi.org/10.1038/s41388-019-0945-9

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