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

• Published in: International journal of oncology Vol. 51; no. 5; pp. 1583 - 1589
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.11.2017; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Angiogenesis; Animals; Apoptosis - drug effects; Apoptosis - radiation effects; Benzamides - administration & dosage; Benzamides - chemical synthesis; Cancer; Cancer therapies; Care and treatment; Cell adhesion & migration; Cell culture; Cell cycle; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - radiation effects; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; cyclin D1; Development and progression; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - radiation effects; FAK1; Focal Adhesion Kinase 1 - antagonists & inhibitors; Focal Adhesion Kinase 1 - genetics; G1 Phase Cell Cycle Checkpoints - drug effects; G1 Phase Cell Cycle Checkpoints - radiation effects; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Growth factors; Health aspects; Humans; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Metastasis; Mice; Ovarian cancer; Phosphorylation; Phosphotransferases; pRb; Proteins; Radiation; Radiation Tolerance - drug effects; Radiation Tolerance - genetics; radiosensitivity; Retina; Retinoblastoma; Studies; Tumor Microenvironment - drug effects; Tumor Microenvironment - radiation effects; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2017.4141

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.