期刊
EMBO MOLECULAR MEDICINE
卷 7, 期 5, 页码 648-669出版社
WILEY
DOI: 10.15252/emmm.201404368
关键词
DDX3; DNA repair; lung cancer; radiation-sensitizing agent; small molecule inhibitor
资金
- Dr. Saal van Swanenberg Foundation
- Dutch Cancer Society [UU 2010-4856]
- DoD [W81XWH-11-1-0272, W81XWH-10-1-0603]
- ACS [122688-RSG-12-196-01-TBG]
- FAMRI
- Maryland Innovation Initiative Award
- Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH) [P30CA006973, UL1 RR025005]
- Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins [1S10RR026824-01]
Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3-overexpressing cells. Importantly, RK-33 in combination with radiation induced tumor regression in multiple mouse models of lung cancer. Mechanistically, loss of DDX3 function either by shRNA or by RK-33 impaired Wnt signaling through disruption of the DDX3--catenin axis and inhibited non-homologous end joiningthe major DNA repair pathway in mammalian somatic cells. Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy.
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