Targeting DDX3 with a small molecule inhibitor for lung cancer therapy

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

doi:10.15252/emmm.201404368

Targeting DDX3 with a small molecule inhibitor for lung cancer therapy

EMBO Mol Med. 2015 May;7(5):648-69. doi: 10.15252/emmm.201404368.

Authors

Guus M Bol¹, Farhad Vesuna², Min Xie², Jing Zeng³, Khaled Aziz³, Nishant Gandhi³, Anne Levine², Ashley Irving², Dorian Korz², Saritha Tantravedi², Marise R Heerma van Voss¹, Kathleen Gabrielson⁴, Evan A Bordt⁵, Brian M Polster⁵, Leslie Cope⁶, Petra van der Groep⁷, Atul Kondaskar⁸, Michelle A Rudek⁶, Ramachandra S Hosmane⁸, Elsken van der Wall⁹, Paul J van Diest¹⁰, Phuoc T Tran¹¹, Venu Raman¹²

Affiliations

¹ Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
² Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.
⁶ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁸ Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, MD, USA.
⁹ Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁰ Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA vraman2@jhmi.edu.

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.

Keywords: DDX3; DNA repair; lung cancer; radiation‐sensitizing agent; small molecule inhibitor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Agents / isolation & purification
Antineoplastic Agents / pharmacology*
Apoptosis
Azepines / isolation & purification
Azepines / pharmacology*
Cell Cycle / drug effects
Cell Cycle Checkpoints
Cell Line
DEAD-box RNA Helicases / antagonists & inhibitors*
Humans
Imidazoles / isolation & purification
Imidazoles / pharmacology*
Lung Neoplasms / drug therapy*
Lung Neoplasms / radiotherapy*
Mice, Nude
Mice, Transgenic
Radiation-Sensitizing Agents / isolation & purification
Radiation-Sensitizing Agents / pharmacology*

Substances

3,7-dihydro-3,7-bis((4-methoxyphenyl)methyl)-2H-diimidazo(4,5-d:4',5'-f)(1,3)diazepin-2-one
Antineoplastic Agents
Azepines
Imidazoles
Radiation-Sensitizing Agents
DDX3X protein, human
DEAD-box RNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding