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 WallPaul J. van Diest, Phuoc T. Tran, Venu Raman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)648-669
Number of pages22
JournalEMBO Molecular Medicine
Volume7
Issue number5
DOIs
StatePublished - May 1 2015

Keywords

  • DDX3
  • DNA repair
  • Lung cancer
  • Radiation-sensitizing agent
  • Small molecule inhibitor

ASJC Scopus subject areas

  • Molecular Medicine

Fingerprint Dive into the research topics of 'Targeting DDX3 with a small molecule inhibitor for lung cancer therapy'. Together they form a unique fingerprint.

Cite this