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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

101 Scopus citations

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 language	English (US)
Pages (from-to)	648-669
Number of pages	22
Journal	EMBO Molecular Medicine
Volume	7
Issue number	5
DOIs	https://doi.org/10.15252/emmm.201404368
State	Published - May 1 2015

Keywords

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

ASJC Scopus subject areas

Molecular Medicine

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10.15252/emmm.201404368

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Bol, G. M., Vesuna, F., Xie, M., Zeng, J., Aziz, K., Gandhi, N., Levine, A., Irving, A., Korz, D., Tantravedi, S., Heerma van Voss, M. R., Gabrielson, K., Bordt, E. A., Polster, B. M., Cope, L., van der Groep, P., Kondaskar, A., Rudek, M. A., Hosmane, R. S., ... Raman, V. (2015). Targeting DDX3 with a small molecule inhibitor for lung cancer therapy. EMBO Molecular Medicine, 7(5), 648-669. https://doi.org/10.15252/emmm.201404368

Bol, GM, Vesuna, F, Xie, M, Zeng, J, Aziz, K, Gandhi, N, Levine, A, Irving, A, Korz, D, Tantravedi, S, Heerma van Voss, MR, Gabrielson, K, Bordt, EA, Polster, BM, Cope, L, van der Groep, P, Kondaskar, A, Rudek, MA, Hosmane, RS, van der Wall, E, van Diest, PJ, Tran, PT & Raman, V 2015, 'Targeting DDX3 with a small molecule inhibitor for lung cancer therapy', EMBO Molecular Medicine, vol. 7, no. 5, pp. 648-669. https://doi.org/10.15252/emmm.201404368

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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.",

keywords = "DDX3, DNA repair, Lung cancer, Radiation-sensitizing agent, Small molecule inhibitor",

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year = "2015",

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doi = "10.15252/emmm.201404368",

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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

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.

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Targeting DDX3 with a small molecule inhibitor for lung cancer therapy

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Keywords

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