Novel focal adhesion kinase 1 inhibitor sensitizes lung cancer cells to radiation in a p53-independent manner

Jung,Seung-Youn; Kho,Seongho; Song,Kyung-Hee; Ahn,Jiyeon; Park,In-Chul; Nam,Ky-Youb; Hwang,Sang-Gu; Nam,Seon-Young; Cho,Seong-Jun; Song,Jie-Young

doi:10.3892/ijo.2017.4141

Novel focal adhesion kinase 1 inhibitor sensitizes lung cancer cells to radiation in a p53-independent manner

Authors:
- Seung-Youn Jung
- Seongho Kho
- Kyung-Hee Song
- Jiyeon Ahn
- In-Chul Park
- Ky-Youb Nam
- Sang-Gu Hwang
- Seon-Young Nam
- Seong-Jun Cho
- Jie-Young Song
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Affiliations: Division of Applied Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea, Division of Basic Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea, Paros I&BT Co., Ltd., 1408, 38 Heungan‑daero 427 beon-gil, Dongan-gu, Anyang-si, Gyeonggi-do 14059, Republic of Korea, Low-Dose Radiation Research Team, Radiation Health Institute, Korea Hydro and Nuclear Power Co., Ltd., Seoul 01450, Republic of Korea
Published online on: September 29, 2017 https://doi.org/10.3892/ijo.2017.4141
Pages: 1583-1589

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Abstract

Focal adhesion kinase 1 (FAK1) is known to promote tumor progression and metastasis by controlling cell movement, invasion, survival and the epithelial-to-mesenchymal transition in the tumor microenvironment. As recent reports imply that FAK1 is highly associated with tumor cell development and malignancy, the inhibition of FAK1 activity could be an effective therapeutic approach for inhibiting the growth and metastasis of tumor cells. In this study, we aimed to determine the effect of a novel synthetic FAK1 inhibitor 2-[2-(2-methoxy-4-morpholin-4-yl-phenylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-N-methyl-benzamide, (MPAP) on lung cancer cells. MPAP suppressed cancer cell proliferation and the phosphorylation of FAK1. Combined treatment with MPAP and irradiation (IR) showed enhanced suppression of cancer cell proliferation in wild-type p53 cells and more intense suppression in p53-null cells. In addition, the combination treatment effectively induced G1 cell cycle arrest in a p53-independent manner. In an in vivo tumor xenograft mouse model, treatment with both MPAP and IR reduced tumor growth more than the treatment with IR or MPAP alone. Overall, these data demonstrate that the radiosensitizing effect of MPAP is mediated by the regulation of retinoblastoma protein (RB) phosphorylation in a p53-independent manner.

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