TY - JOUR
T1 - Targeting DDX3 with a small molecule inhibitor for lung cancer therapy
AU - Bol, Guus M.
AU - Vesuna, Farhad
AU - Xie, Min
AU - Zeng, Jing
AU - Aziz, Khaled
AU - Gandhi, Nishant
AU - Levine, Anne
AU - Irving, Ashley
AU - Korz, Dorian
AU - Tantravedi, Saritha
AU - Heerma van Voss, Marise R.
AU - Gabrielson, Kathleen
AU - Bordt, Evan A.
AU - Polster, Brian M.
AU - Cope, Leslie
AU - van der Groep, Petra
AU - Kondaskar, Atul
AU - Rudek, Michelle A.
AU - Hosmane, Ramachandra S.
AU - van der Wall, Elsken
AU - van Diest, Paul J.
AU - Tran, Phuoc T.
AU - Raman, Venu
N1 - Publisher Copyright:
© 2015 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
KW - DDX3
KW - DNA repair
KW - Lung cancer
KW - Radiation-sensitizing agent
KW - Small molecule inhibitor
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U2 - 10.15252/emmm.201404368
DO - 10.15252/emmm.201404368
M3 - Article
C2 - 25820276
AN - SCOPUS:84928987020
SN - 1757-4676
VL - 7
SP - 648
EP - 669
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 5
ER -