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Abstract
PURPOSE:
The identification of novel targets for developing synergistic drug-radiation combinations would pave the way to overcome tumor radioresistance. We conducted cell-based screening of a human kinome siRNA library to identify a radiation-specific kinase that has a synergistic toxic effect with radiation upon inhibition and is not essential for cell survival in the absence of radiation.

EXPERIMENTAL DESIGN:
Unbiased RNAi screening was performed by transfecting A549 cells with a human kinome siRNA library followed by irradiation. Radiosensitizing effects of a target gene and involved mechanisms were examined.

RESULTS:
We identified the nonreceptor protein tyrosine kinase FES (FEline Sarcoma oncogene) as a radiosensitizing target. The expression of FES was increased in response to irradiation. Cell viability and clonogenic survival after irradiation were significantly decreased by FES knockdown in lung and pancreatic cancer cell lines. In contrast, FES depletion alone did not significantly affect cell proliferation without irradiation. An inducible RNAi mouse xenograft model verified in vivo radiosensitizing effects. FES-depleted cells showed increased apoptosis, DNA damage, G2-M phase arrest, and mitotic catastrophe after irradiation. FES depletion promoted radiation-induced reactive oxygen species formation, which resulted in phosphorylation of S6K and MDM2. The radiosensitizing effect of FES knockdown was partially reversed by inhibition of S6K activity. Consistent with the increase in phosphorylated MDM2, an increase in nuclear p53 levels was observed, which appears to contribute increased radiosensitivity of FES-depleted cells.

CONCLUSIONS:
We uncovered that inhibition of FES could be a potential strategy for inducing radiosensitization in cancer. Our results provide the basis for developing novel radiosensitizers.

Author information

Kim BH#1,2, Kim YJ#3,4, Kim MH4, Na YR5, Jung D5, Seok SH5, Kim J6, Kim HJ7,8.
1
Department of Radiation Oncology, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
2
Department of Radiation Oncology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
3
Department of Ophthalmology, Institute of Vision Research, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
4
Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
5
Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University Medical College, Seoul, Republic of Korea.
6
Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea. khjae@snu.ac.kr joonkim@kaist.ac.kr.
7
Department of Radiation Oncology, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea. khjae@snu.ac.kr joonkim@kaist.ac.kr.
8
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
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Contributed equally