Targeting <scp>DDX</scp>3 with a small molecule inhibitor for lung cancer therapy

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

doi:10.15252/emmm.201404368

Cited by 172 publications

(253 citation statements)

References 52 publications

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“…Genetic alterations in DDX3X are in stark contrast with the reports on overexpression of DDX3 in several cancers as compared to the normal tissue of origin[47]. High DDX3 expression correlated with high grade and worse overall survival in breast[48] and lung cancer[49]. DDX3 mutations were not frequently detected in genome wide mutation analyses in these cancer types.…”

Section: Role Of Dead/h Box Proteins In Translating the Cancer Genomementioning

confidence: 94%

Targeting RNA helicases in cancer: The translation trap

Voss

Diest

Raman

2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Cancer cells are reliant on the cellular translational machinery for both global elevation of protein synthesis and the translation of specific mRNAs that promote tumor cell survival. Targeting translational control in cancer is therefore increasingly recognized as a promising therapeutic strategy. In this regard, DEAD/H box RNA helicases are a very interesting group of proteins, with several family members regulating mRNA translation in cancer cells. In this review, we delineate the mechanisms by which DEAD/H box proteins modulate oncogenic translation and how inhibition of these RNA helicases can be exploited for anti-cancer therapeutics.

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Section: Role Of Dead/h Box Proteins In Translating the Cancer Genomementioning

confidence: 94%

Targeting RNA helicases in cancer: The translation trap

Voss

Diest

Raman

2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…It has been reported that DDX3X is an important target for the development of broad-spectrum antiviral agents [38]. In lung cancer, a small molecule inhibitor (RK-33) targeting DDX3X was found to be effective in inducing apoptosis and promoting sensitization to radiation in DDX3X-overexpressing cell lines [39]. Similarly, targeted therapy for NKTCL based on mutant DDX3X is also promising considering its pathological role in this disease.…”

Section: Ddx3xmentioning

confidence: 99%

Frequent Mutations in Natural Killer/T Cell Lymphoma

Zhang¹,

Li²,

Xue³

et al. 2018

Cell Physiol Biochem

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Extranodal natural killer (NK)/T cell lymphoma (ENKTL-NT or NKTCL), with its aggressive nature and poor prognosis, has been widely studied to discover more effective treatment options. Various somatic gene alterations have been identified by traditional Sanger sequencing. However, recently, novel gene mutations in NKTCL have been revealed by next-generation sequencing (NGS) technology, suggesting the potential for novel targeted therapies. This review discusses recurrent aberrations in NKTCL detected by NGS, which can be categorized into three main groups, specifically, tumor suppressors (TP53, DDX3X, and MGA), the JAK/STAT cascade, and epigenetic modifiers (KMT2D, BCOR, ARID1A, and EP300). Some epigenetic dysregulation and DDX3X mutation, which have been rarely identified by traditional sequencing technology, were recently uncovered with high frequencies by NGS. In this review, we summarize the mutational frequencies of various genes in NKTCL. In general, based on our analysis, BCOR is the most frequently mutated gene (16.9%), followed by TP53 (14.7%), and DDX3X (13.6%). The characterization of such genes provides new insight into the pathogenesis of this disease and indicates new biomarkers or therapeutic targets.

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“…Messenger RNA molecules containing especially long or structured 5Ј leader sequences are particularly sensitive to DDX3 activity (6,7,12,13). DDX3X is frequently mutated in numerous cancer types (5), such as chronic lymphocytic leukemia (14 -16), natural killer/T-cell lymphoma (17), head and neck squamous cell carcinoma (18,19), and lung cancer (20). DDX3X is also one of the most frequently mutated genes in the highly malignant brain tumor medulloblastoma (21)(22)(23)(24).…”

mentioning

confidence: 99%

Autoinhibitory Interdomain Interactions and Subfamily-specific Extensions Redefine the Catalytic Core of the Human DEAD-box Protein DDX3

Floor

Condon

Sharma

et al. 2016

Journal of Biological Chemistry

109

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DEAD-box proteins utilize ATP to bind and remodel RNA and RNA-protein complexes. All DEAD-box proteins share a conserved core that consists of two RecA-like domains. The core is flanked by subfamily-specific extensions of idiosyncratic function. The Ded1/DDX3 subfamily of DEAD-box proteins is of particular interest as members function during protein translation, are essential for viability, and are frequently altered in human malignancies. Here, we define the function of the subfamily-specific extensions of the human DEAD-box protein DDX3. We describe the crystal structure of the subfamily-specific core of wild-type DDX3 at 2.2 Å resolution, alone and in the presence of AMP or nonhydrolyzable ATP. These structures illustrate a unique interdomain interaction between the two ATPase domains in which the C-terminal domain clashes with the RNA-binding surface. Destabilizing this interaction accelerates RNA duplex unwinding, suggesting that it is present in solution and inhibitory for catalysis. We use this core fragment of DDX3 to test the function of two recurrent medulloblastoma variants of DDX3 and find that both inactivate the protein in vitro and in vivo. Taken together, these results redefine the structural and functional core of the DDX3 subfamily of DEADbox proteins.DEAD-box proteins are ATP-dependent RNA-binding proteins that remodel RNA structures and RNA-protein complexes, stably clamp RNA, and promote fluidity within RNA granules (1-3). The human DEAD-box protein DDX3 (encoded by DDX3X) and its yeast ortholog Ded1p have been implicated in numerous functions including translation initiation (4 -12). Messenger RNA molecules containing especially long or structured 5Ј leader sequences are particularly sensitive to DDX3 activity (6,7,12,13). DDX3X is frequently mutated in numerous cancer types (5), such as chronic lymphocytic leukemia (14 -16), natural killer/T-cell lymphoma (17), head and neck squamous cell carcinoma (18,19), and lung cancer (20). DDX3X is also one of the most frequently mutated genes in the highly malignant brain tumor medulloblastoma (21-24). In medulloblastoma, many mutations are predicted to inactivate DDX3, and some have been demonstrated to diminish activities in vitro (17,25).DEAD-box proteins are defined by 12 different motifs that function in ATP binding or hydrolysis and RNA binding, or couple ATP and RNA binding (1). Outside of these conserved motifs, each DEAD-box protein subfamily has unique tails that lie N-or C-terminal to the helicase core and contain elements that define the unique properties of that subfamily. For example, DDX21 has a GUCT domain in its C-terminal extension (26, 27), DDX5 has tandem P68HR domains in its C-terminal extension, and DDX43 has a KH1 domain in its N-terminal extension. However, as the tails of each DEAD-box protein subfamily are idiosyncratic, whereas the cores are very similar (28,29), it is essential to study individual subfamilies of DEAD-box proteins in detail to understand the role of subfamily-specific tails.DDX3 is a member of the Ded1/DDX...

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Targeting DDX3 with a small molecule inhibitor for lung cancer therapy

Cited by 172 publications

References 52 publications

Targeting RNA helicases in cancer: The translation trap

Targeting RNA helicases in cancer: The translation trap

Frequent Mutations in Natural Killer/T Cell Lymphoma

Autoinhibitory Interdomain Interactions and Subfamily-specific Extensions Redefine the Catalytic Core of the Human DEAD-box Protein DDX3

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