Targeting DDX3 with a small molecule inhibitor for lung cancer therapy

EMBO Molecular Medicine

Guus M Bol⁴  Farhad Vesuna⁴  Min Xie⁴  Jing Zeng⁶  Khaled Aziz⁶  Nishant Gandhi⁶  Anne Levine⁴  Ashley Irving⁴  Dorian Korz⁴  Saritha Tantravedi⁴  Marise R Heerma van Voss⁴  Kathleen Gabrielson¹  Evan A Bordt⁷  Brian M Polster⁷  Leslie Cope⁸  Petra van der Groep³  Atul Kondaskar⁵  Michelle A Rudek⁸  Ramachandra S Hosmane⁵  Elsken van der Wall²  Paul J van Diest³  Phuoc T Tran⁶ 

[1] Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands;Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands;Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, MD, USA;Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA;Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

关键词: DDX3;    DNA repair;    lung cancer;    radiation‐sensitizing agent;    small molecule inhibitor;   

DOI  :  10.15252/emmm.201404368

来源: Wiley

【 摘 要 】

Abstract

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.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.