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...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201404368 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Guus M Bol |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e07c631e5fec4cceaa092c7b616dd2dc |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-e07c631e5fec4cceaa092c7b616dd2dc2025-08-20T03:05:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-03-017564866910.15252/emmm.201404368Targeting DDX3 with a small molecule inhibitor for lung cancer therapyGuus M Bol0Farhad Vesuna1Min Xie2Jing Zeng3Khaled Aziz4Nishant Gandhi5Anne Levine6Ashley Irving7Dorian Korz8Saritha Tantravedi9Marise R Heerma van Voss10Kathleen Gabrielson11Evan A Bordt12Brian M Polster13Leslie Cope14Petra van der Groep15Atul Kondaskar16Michelle A Rudek17Ramachandra S Hosmane18Elsken van der Wall19Paul J van Diest20Phuoc T Tran21Venu Raman22Department of Radiology and Radiological Science, Johns Hopkins University School of MedicineDepartment of Radiology and Radiological Science, Johns Hopkins University School of MedicineDepartment of Radiology and Radiological Science, Johns Hopkins University School of MedicineDepartment of Radiation Oncology, Johns Hopkins University School of MedicineDepartment of Radiation Oncology, Johns Hopkins University School of MedicineDepartment of Radiation Oncology, Johns Hopkins University School of MedicineDepartment of Radiology and Radiological Science, Johns Hopkins University School of MedicineDepartment of Radiology and Radiological Science, Johns Hopkins University School of MedicineDepartment of Radiology and Radiological Science, Johns Hopkins University School of MedicineDepartment of Radiology and Radiological Science, Johns Hopkins University School of MedicineDepartment of Radiology and Radiological Science, Johns Hopkins University School of MedicineDepartment of Molecular and Comparative Pathobiology, Johns Hopkins University School of MedicineDepartment of Anesthesiology, University of Maryland School of MedicineDepartment of Anesthesiology, University of Maryland School of MedicineDepartment of Oncology, Johns Hopkins University School of MedicineDepartment of Pathology, University Medical Center UtrechtDepartment of Chemistry & Biochemistry, University of MarylandDepartment of Oncology, Johns Hopkins University School of MedicineDepartment of Chemistry & Biochemistry, University of MarylandDepartment of Internal Medicine, University Medical Center UtrechtDepartment of Pathology, University Medical Center UtrechtDepartment of Radiation Oncology, Johns Hopkins University School of MedicineDepartment of Radiology and Radiological Science, Johns Hopkins University School of MedicineAbstract 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.https://doi.org/10.15252/emmm.201404368DDX3DNA repairlung cancerradiation‐sensitizing agentsmall molecule inhibitor |
| spellingShingle | 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 Targeting DDX3 with a small molecule inhibitor for lung cancer therapy EMBO Molecular Medicine DDX3 DNA repair lung cancer radiation‐sensitizing agent small molecule inhibitor |
| title | Targeting DDX3 with a small molecule inhibitor for lung cancer therapy |
| title_full | Targeting DDX3 with a small molecule inhibitor for lung cancer therapy |
| title_fullStr | Targeting DDX3 with a small molecule inhibitor for lung cancer therapy |
| title_full_unstemmed | Targeting DDX3 with a small molecule inhibitor for lung cancer therapy |
| title_short | Targeting DDX3 with a small molecule inhibitor for lung cancer therapy |
| title_sort | targeting ddx3 with a small molecule inhibitor for lung cancer therapy |
| topic | DDX3 DNA repair lung cancer radiation‐sensitizing agent small molecule inhibitor |
| url | https://doi.org/10.15252/emmm.201404368 |
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