Targeting DDX3 with a small molecule inhibitor for lung cancer therapy

• DOI: 10.15252/emmm.201404368
• Publication Date: 2015-03-28T18:09:06Z
• Authors: Guus M Bol; Farhad Vesuna; Min Xie; Jing Zeng; Khaled Aziz; Nishant Gandhi; Anne Levine; Ashley Irving; Dorian Korz; Saritha Tantravedi; Marise R Heerma v...; Kathleen Gabrielson; Evan A Bordt; Brian M Polster; Leslie Cope; Petra van der Groep; Atul Kondaskar; Michelle A Rudek; Ramachandra S Hos...; Elsken van der Wall; Paul J van Diest; Phuoc T Tran; Venu Raman
• Keywords: Medicine (General); Radiation-Sensitizing Agents; Lung Neoplasms; DNA repair; Mice, Nude; Antineoplastic Agents; Apoptosis; Mice, Transgenic; QH426-470; Cell Line; DEAD-box RNA Helicases; 03 medical and health sciences; R5-920; DDX3; Genetics; Animals; Humans; Research Articles; Radiation-sensitizing agent; radiation‐sensitizing agent; 0303 health sciences; Cell Cycle; Imidazoles; small molecule inhibitor; Azepines; Cell Cycle Checkpoints; 3. Good health; lung cancer; Molecular Medicine; Small molecule inhibitor; Lung cancer

AbstractLung 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–β‐catenin axis and inhibited non‐homologous end joining—the 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.