title: Targeting DDX3 with a small molecule inhibitor for lung cancer therapy.
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.
authors.affiliation: 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.
authors.forename: Guus M
authors.initials: GM
authors.lastname: Bol
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Farhad
authors.initials: F
authors.lastname: Vesuna
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Khaled
authors.initials: K
authors.lastname: Aziz
authors.affiliation: Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Nishant
authors.initials: N
authors.lastname: Gandhi
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Levine
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Irving
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Dorian
authors.initials: D
authors.lastname: Korz
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Saritha
authors.initials: S
authors.lastname: Tantravedi
authors.affiliation: 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.
authors.forename: Marise R
authors.initials: MR
authors.lastname: Heerma van Voss
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gabrielson
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Evan A
authors.initials: EA
authors.lastname: Bordt
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Polster
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Cope
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: van der Groep
authors.affiliation: Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, MD, USA.
authors.forename: Atul
authors.initials: A
authors.lastname: Kondaskar
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, MD, USA.
authors.forename: Ramachandra S
authors.initials: RS
authors.lastname: Hosmane
authors.affiliation: Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.affiliation: 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.
authors.forename: Phuoc T
authors.initials: PT
authors.lastname: Tran
authors.affiliation: 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.
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis; D001381:Azepines / Q000302:isolation & purification / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000302:isolation & purification / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D008819:Mice, Nude; D008822:Mice, Transgenic; D011838:Radiation-Sensitizing Agents / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: C000603512:3,7-dihydro-3,7-bis((4-methoxyphenyl)methyl)-2H-diimidazo(4,5-d:4',5'-f)(1,3)diazepin-2-one; D000970:Antineoplastic Agents; D001381:Azepines; D007093:Imidazoles; D011838:Radiation-Sensitizing Agents; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases
keywords: DDX3; DNA repair; lung cancer; radiation‐sensitizing agent; small molecule inhibitor
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