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

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 - EMBO Mol Med (2015)

Bottom Line: We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

No MeSH data available.


Related in: MedlinePlus

RK-33 induces radiosensitization in preclinical mouse models of lung cancerSchematic describing the Twist1/KrasG12D-inducible mouse model.Confirmation of high expression of Twist1 and DDX3 in the lung tumors of the transgenic Twist1/KrasG12D mouse. Scale bar is 100 μm.Treatment schedule for mice receiving hypofractionated radiation (SABR). Stars are intraperitoneal (i.p.) injections with RK-33.Micro-CT images of transgenic Twist1/KrasG12D mice treated as in (C), before treatment and 1 week after treatment. Tumors are indicated by arrows and confirmed by H&E staining of lung sections (lower panel). Scale bar is 250 μm.Quantification of tumor volume measured by micro-CT in Twist1/KrasG12D mice, as shown in (D). Significance was assessed by two-sided, unpaired t-test. Error bars represent SD.An orthotopic lung tumor model was generated using A549 human lung cancer cells and treated as in (C). Figure displays H&E staining of lung sections from radiation-treated (upper panel) and RK-33- and radiation-treated mice (lower panel). Scale bar is 2 mm.Quantification of tumor burden (as tumor surface divided by total lung surface) in orthotopic A549 lung cancer mouse model, as shown in (F). Significance was assessed by two-sided, unpaired t-test. Error bars represent SD.Treatment schedule for mice receiving fractionated radiation in 10 fractions. Stars indicate i.p. injections with RK-33. Downward lightning bolts indicate 3-Gy radiation fractions.Micro-CT images of transgenic Twist1/KrasG12D mice treated as in (H), before treatment and 1 week after treatment.Quantification of tumor volume measured by micro-CT in Twist1/KrasG12D mice, as shown in (I) and expressed as relative tumor size. Significance was assessed by two-sided, unpaired t-test. Error bars represent SEM.
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fig06: RK-33 induces radiosensitization in preclinical mouse models of lung cancerSchematic describing the Twist1/KrasG12D-inducible mouse model.Confirmation of high expression of Twist1 and DDX3 in the lung tumors of the transgenic Twist1/KrasG12D mouse. Scale bar is 100 μm.Treatment schedule for mice receiving hypofractionated radiation (SABR). Stars are intraperitoneal (i.p.) injections with RK-33.Micro-CT images of transgenic Twist1/KrasG12D mice treated as in (C), before treatment and 1 week after treatment. Tumors are indicated by arrows and confirmed by H&E staining of lung sections (lower panel). Scale bar is 250 μm.Quantification of tumor volume measured by micro-CT in Twist1/KrasG12D mice, as shown in (D). Significance was assessed by two-sided, unpaired t-test. Error bars represent SD.An orthotopic lung tumor model was generated using A549 human lung cancer cells and treated as in (C). Figure displays H&E staining of lung sections from radiation-treated (upper panel) and RK-33- and radiation-treated mice (lower panel). Scale bar is 2 mm.Quantification of tumor burden (as tumor surface divided by total lung surface) in orthotopic A549 lung cancer mouse model, as shown in (F). Significance was assessed by two-sided, unpaired t-test. Error bars represent SD.Treatment schedule for mice receiving fractionated radiation in 10 fractions. Stars indicate i.p. injections with RK-33. Downward lightning bolts indicate 3-Gy radiation fractions.Micro-CT images of transgenic Twist1/KrasG12D mice treated as in (H), before treatment and 1 week after treatment.Quantification of tumor volume measured by micro-CT in Twist1/KrasG12D mice, as shown in (I) and expressed as relative tumor size. Significance was assessed by two-sided, unpaired t-test. Error bars represent SEM.

Mentions: To assess whether RK-33 could be a clinically useful radiosensitizer, we evaluated RK-33 in combination with different radiation doses in both an immune competent Twist1/KrasG12D autochthonous lung tumor model (Fig6A) (Tran et al, 2012) and an orthotopic human xenograft model for lung cancer. This autochthonous model harbors a KrasG12D mutation and overexpresses Twist1 and Ddx3, which made it a suitable model to test efficacy of RK-33 (Fig6B).


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

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 - EMBO Mol Med (2015)

RK-33 induces radiosensitization in preclinical mouse models of lung cancerSchematic describing the Twist1/KrasG12D-inducible mouse model.Confirmation of high expression of Twist1 and DDX3 in the lung tumors of the transgenic Twist1/KrasG12D mouse. Scale bar is 100 μm.Treatment schedule for mice receiving hypofractionated radiation (SABR). Stars are intraperitoneal (i.p.) injections with RK-33.Micro-CT images of transgenic Twist1/KrasG12D mice treated as in (C), before treatment and 1 week after treatment. Tumors are indicated by arrows and confirmed by H&E staining of lung sections (lower panel). Scale bar is 250 μm.Quantification of tumor volume measured by micro-CT in Twist1/KrasG12D mice, as shown in (D). Significance was assessed by two-sided, unpaired t-test. Error bars represent SD.An orthotopic lung tumor model was generated using A549 human lung cancer cells and treated as in (C). Figure displays H&E staining of lung sections from radiation-treated (upper panel) and RK-33- and radiation-treated mice (lower panel). Scale bar is 2 mm.Quantification of tumor burden (as tumor surface divided by total lung surface) in orthotopic A549 lung cancer mouse model, as shown in (F). Significance was assessed by two-sided, unpaired t-test. Error bars represent SD.Treatment schedule for mice receiving fractionated radiation in 10 fractions. Stars indicate i.p. injections with RK-33. Downward lightning bolts indicate 3-Gy radiation fractions.Micro-CT images of transgenic Twist1/KrasG12D mice treated as in (H), before treatment and 1 week after treatment.Quantification of tumor volume measured by micro-CT in Twist1/KrasG12D mice, as shown in (I) and expressed as relative tumor size. Significance was assessed by two-sided, unpaired t-test. Error bars represent SEM.
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Related In: Results  -  Collection

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fig06: RK-33 induces radiosensitization in preclinical mouse models of lung cancerSchematic describing the Twist1/KrasG12D-inducible mouse model.Confirmation of high expression of Twist1 and DDX3 in the lung tumors of the transgenic Twist1/KrasG12D mouse. Scale bar is 100 μm.Treatment schedule for mice receiving hypofractionated radiation (SABR). Stars are intraperitoneal (i.p.) injections with RK-33.Micro-CT images of transgenic Twist1/KrasG12D mice treated as in (C), before treatment and 1 week after treatment. Tumors are indicated by arrows and confirmed by H&E staining of lung sections (lower panel). Scale bar is 250 μm.Quantification of tumor volume measured by micro-CT in Twist1/KrasG12D mice, as shown in (D). Significance was assessed by two-sided, unpaired t-test. Error bars represent SD.An orthotopic lung tumor model was generated using A549 human lung cancer cells and treated as in (C). Figure displays H&E staining of lung sections from radiation-treated (upper panel) and RK-33- and radiation-treated mice (lower panel). Scale bar is 2 mm.Quantification of tumor burden (as tumor surface divided by total lung surface) in orthotopic A549 lung cancer mouse model, as shown in (F). Significance was assessed by two-sided, unpaired t-test. Error bars represent SD.Treatment schedule for mice receiving fractionated radiation in 10 fractions. Stars indicate i.p. injections with RK-33. Downward lightning bolts indicate 3-Gy radiation fractions.Micro-CT images of transgenic Twist1/KrasG12D mice treated as in (H), before treatment and 1 week after treatment.Quantification of tumor volume measured by micro-CT in Twist1/KrasG12D mice, as shown in (I) and expressed as relative tumor size. Significance was assessed by two-sided, unpaired t-test. Error bars represent SEM.
Mentions: To assess whether RK-33 could be a clinically useful radiosensitizer, we evaluated RK-33 in combination with different radiation doses in both an immune competent Twist1/KrasG12D autochthonous lung tumor model (Fig6A) (Tran et al, 2012) and an orthotopic human xenograft model for lung cancer. This autochthonous model harbors a KrasG12D mutation and overexpresses Twist1 and Ddx3, which made it a suitable model to test efficacy of RK-33 (Fig6B).

Bottom Line: We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

No MeSH data available.


Related in: MedlinePlus