Details

Autor(en) / Beteiligte

• Bol, Guus M
• Vesuna, Farhad
• Xie, Min
• Zeng, Jing
• Aziz, Khaled
• Gandhi, Nishant
• Levine, Anne
• Irving, Ashley
• Korz, Dorian
• Tantravedi, Saritha
• Heerma van Voss, Marise R
• Gabrielson, Kathleen
• Bordt, Evan A
• Polster, Brian M
• Cope, Leslie
• Groep, Petra
• Kondaskar, Atul
• Rudek, Michelle A
• Hosmane, Ramachandra S
• Wall, Elsken
• Diest, Paul J
• Tran, Phuoc T
• Raman, Venu

Titel

Targeting DDX3 with a small molecule inhibitor for lung cancer therapy

Ist Teil von

• EMBO molecular medicine, 2015-05, Vol.7 (5), p.648-669

Ort / Verlag

England: BlackWell Publishing Ltd

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• 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–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. Synopsis The RNA helicase DDX3 is a new independent marker of lung cancer and targeted chemotherapy option. The novel inhibitor RK‐33, combined with radiation therapy, induces tumor regression in lung cancer models, with no toxicity at the therapeutic dose. The RNA helicase DDX3 is overexpressed in lung cancer and is associated with lower survival in lung cancer patients. Knockdown of DDX3 in highly aggressive lung cancer cell lines (H1299 and A549) curbed their colony‐forming abilities. A small molecule inhibitor of DDX3, RK‐33, designed to bind to the nucleotide‐binding site within the DDX3 protein was synthesized. RK‐33 was able to induce cell cycle arrest causing apoptosis in aggressive lung cancer, but not in normal cells, and promoted sensitization to radiation in DDX3‐overexpressing cells. Mechanistically, RK‐33 inhibited non‐homologous end joining and impaired Wnt signaling by disrupting the DDX3–β‐catenin axis. RK‐33 in combination with radiation, induced tumor regression in multiple mouse models of lung cancer, while showing no toxicity at the therapeutic dose. The RNA helicase DDX3 is a new independent marker of lung cancer and targeted chemotherapy option. The novel inhibitor RK‐33, combined with radiation therapy, induces tumor regression in lung cancer models, with no toxicity at the therapeutic dose.