Targeting DDX3 with a small molecule inhibitor for lung cancer therapy.

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

doi:10.15252/emmm.201404368

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.

Highlights

Lung cancer is the most common cancer worldwide, and it claims more lives than prostate, colon, and breast cancer combined (Siegel et al, 2013)
DDX3 is expressed in lung cancer cell lines (H23, H1299, H460, A549, and H3255) but not in the normal lung cell line HBEC (Fig 1A)
One such gene is DDX3, a member of the RNA helicase family, which we have shown to be dysregulated in breast cancer cell lines, up-regulated by HIF-1a, and involved in cancer maintenance and metastasis (Botlagunta et al, 2008, 2011; Bol et al, 2013)

Summary

Introduction

Lung cancer is the most common cancer worldwide, and it claims more lives than prostate, colon, and breast cancer combined (Siegel et al, 2013). Depending on tumor type and stage, the treatment for lung cancer patients typically consists of surgery or chemoradiation. Surgical resection offers the best long-term survival for lung cancer patients, only a subset of these patients are considered operable and chemoradiation is the only option for the majority of patients (Manser et al, 2005). Recent advances in radiation therapy such as stereotactic body radiation therapy (SBRT) or stereotactic ablative radiation therapy (SABR) have shown increased efficacy to reduce lung tumor burden and offer a new therapeutic modality to non-surgical patients. Clinical experiences with SBRT in early-stage lung cancer and oligometastatic cancer have demonstrated excellent local control of greater than 90% (Timmerman et al, 2010). Because of increased toxicity with delivery of SBRT to large treatment targets or following re-treatment, there has been an ongoing search for tumor-selective radiation sensitizers that would enable the use of lower dose per fraction with increased efficacy (Senthi et al, 2012)

Methods

Results

Conclusion