NVP-BSK805, an Inhibitor of JAK2 Kinase, Significantly Enhances the Radiosensitivity of Esophageal Squamous Cell Carcinoma in vitro and in vivo

Abstract

Purpose

Radiotherapy is one major curative treatment modality for esophageal squamous cell carcinoma (ESCC) patients. This study aimed to find out small-molecular kinase inhibitors, which can significantly enhance the radiosensitivity of ESCC in vitro and in vivo.

Materials and Methods

Ninety-three kinase inhibitors were tested for their radiosensitizing effect in ESCC cells through high-content screening. The radiosensitizing effect of kinase inhibitors was investigated in vitro by detection of DNA double-strand breaks (DSBs) and clonogenic survival assay. By the establishment of xenograft tumor models in BALB/c nude mice, the radiosensitizing effect of kinase inhibitors was investigated in vivo.

Results

Among the 93 kinase inhibitors tested, we found NVP-BSK805, an inhibitor of JAK2 kinase, significantly radiosensitized ESCC cells through enhancing DSBs, inhibiting DNA damage repair and arresting cell cycle in G2/M or G0/G1 phase. After treatment with NVP-BSK805, ESCC cells showed decreased clonogenic survival and delayed tumor growth in vivo. JAK2 kinase was highly expressed in tumor tissues of ESCC patients, while rarely expressed in matched normal esophageal epithelial tissues. Survival analysis revealed JAK2 kinase as a prognostic factor of ESCC patients treated with chemoradiotherapy.

Conclusion

Our study discovered JAK2 kinase as an attractive target to enhance the radiosensitivity of ESCC cells in vitro and in vivo.

Keywords:

• ESCC
• radioresistance
• JAK2
• NVP-BSK805
• DNA damage repair

Acknowledgments

This work was financially supported by National Natural Science Foundation of China (No. 81672994), Zhejiang Provincial Natural Sciences Foundation of China (No. LZ15H220001 and No. LY18H310012), Zhejiang Provincial Medical Scientific Research Foundation of China (No. 2015PYA009), Hangzhou City Medical Scientific Research Foundation of Zhejiang Province, China (No. 20180533B67) and Hangzhou City Scientific Technology Research Foundation of Zhejiang Province, China (No. 20150733Q63).

The abstract of this paper was presented at ASTRO’s 2017 Annual Meeting as a poster presentation/conference talk with interim findings. The poster’s abstract was published in “Poster Abstracts” in International Journal of Radiation Oncology • Biology • Physics, Vol. 99, Issue 2, E630–E631.

Disclosure

The authors declare that they have no potential or actual conflicts of interest.