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Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies Emanuela Dylgjeri1,2, Christopher Mcnair1,2, Jonathan F

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Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies Emanuela Dylgjeri1,2, Christopher Mcnair1,2, Jonathan F Published OnlineFirst July 2, 2019; DOI: 10.1158/1078-0432.CCR-18-2207 Translational Cancer Mechanisms and Therapy Clinical Cancer Research Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies Emanuela Dylgjeri1,2, Christopher McNair1,2, Jonathan F. Goodwin1,2, Heather K. Raymon3, Peter A. McCue4, Ayesha A. Shafi1,2, Benjamin E. Leiby2,5, Renee de Leeuw1,2, Vishal Kothari4, Jennifer J. McCann1,2, Amy C. Mandigo1,2, Saswati N. Chand1,2, Matthew J. Schiewer1,2, Lucas J. Brand1,2, Irina Vasilevskaya1,2, Nicolas Gordon1,2, Talya S. Laufer1,2, Leonard G. Gomella4, Costas D. Lallas4, Edouard J. Trabulsi4, Felix Y. Feng6,7,8, Ellen H. Filvaroff3, Kristin Hege3, Dana Rathkopf9, and Karen E. Knudsen1,2,4,10 Abstract Purpose: DNA-dependent protein kinase catalytic subunit DNA-PK suppresses tumor growth both in vitro, in vivo, and (DNA-PK) is a pleiotropic kinase involved in DNA repair and ex vivo; (iii) DNA-PK transcriptionally regulates the known transcriptional regulation. DNA-PK is deregulated in selected DNA-PK–mediated functions as well as novel cancer-related cancer types and is strongly associated with poor outcome. The pathways that promote tumor growth; (iv) dual targeting of underlying mechanisms by which DNA-PK promotes aggres- DNA-PK/TOR kinase (TORK) transcriptionally upregulates sive tumor phenotypes are not well understood. Here, unbi- androgen signaling, which can be mitigated using the andro- ased molecular investigation in clinically relevant tumor mod- gen receptor (AR) antagonist enzalutamide; (v) cotargeting AR els reveals novel functions of DNA-PK in cancer. and DNA-PK/TORK leads to the expansion of antitumor Experimental Design: DNA-PK function was modulated effects, uncovering the modulation of novel, highly relevant using both genetic and pharmacologic methods in a series of protumorigenic cancer pathways; and (viii) cotargeting in vitro models, in vivo xenografts, and patient-derived explants DNA-PK/TORK and AR has cooperative growth inhibitory (PDE), and the impact on the downstream signaling and effects in vitro and in vivo. cellular cancer phenotypes was discerned. Data obtained were Conclusions: These findings uncovered novel DNA-PK used to develop novel strategies for combinatorial targeting of transcriptional regulatory functions and led to the develop- DNA-PK and hormone signaling pathways. ment of a combinatorial therapeutic strategy for patients with Results: Key findings reveal that (i) DNA-PK regulates advanced prostate cancer, currently being tested in the clinical tumor cell proliferation; (ii) pharmacologic targeting of setting. Introduction Multiple DNA damage repair (DDR) mechanisms have been 1 Department of Cancer Biology at Thomas Jefferson University, Philadelphia, selected for through evolution to preserve genomic integrity. DNA 2 Pennsylvania. Sidney Kimmel Cancer Center at Thomas Jefferson University, double-strand breaks (DSB) are the most deleterious and toxic Philadelphia, Pennsylvania. 3Celgene Corporation, San Francisco, California. 4Department of Urology, Sidney Kimmel Cancer Center Thomas Jefferson forms of damage that, if left unrepaired, lead to cell-cycle arrest and University, Philadelphia, Pennsylvania. 5Department of Pharmacology and cell death (1, 2). Two main pathways are employed to repair DSB: Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Penn- homologous recombination (HR), which utilizes a sister chroma- sylvania. 6Department of Radiation Oncology, University of California, San tid in close proximity as a template resulting in high-fidelity DSB 7 Francisco, San Francisco, California. Department of Urology, University of repair (3, 4); and nonhomologous end-joining (NHEJ), which 8 California, San Francisco, San Francisco, California. Department of Medicine, does not require a sister chromatid template resulting in a more University of California, San Francisco, San Francisco, California. 9Memorial Sloan Kettering Cancer Center, New York, New York. 10Departments of Medical error-prone form of repair that can occur throughout the cell Oncology and Radiation Oncology, Thomas Jefferson University, Philadelphia, cycle (5, 6). Although both the processes aid in maintaining Pennsylvania. genomic integrity in normal cells, cancer cells utilize these pro- Note: Supplementary data for this article are available at Clinical Cancer cesses, including upregulation of key DDR proteins, to acquire Research Online (http://clincancerres.aacrjournals.org/). more aggressive phenotypes, and develop resistance to DNA- damaging agents (7). Therefore, targeting the DNA repair machin- Corresponding Author: Karen E. Knudsen, Thomas Jefferson University, 233 South 10th Street, Bluemle (BLSB) 1050, Philadelphia, PA 19107. Phone: 215-503- ery and/or its components that are deregulated in cancer has the 5692; Fax: 215-923-4498; E-mail: [email protected] potential to be employed as anticancer therapeutic strategies. Among many DDR proteins deregulated in cancer, DNA- Clin Cancer Res 2019;25:5623–37 dependent protein kinase catalytic subunit (DNA-PKcs, referred doi: 10.1158/1078-0432.CCR-18-2207 to as DNA-PK herein), a key DNA repair protein involved in NHEJ, Ó2019 American Association for Cancer Research. is known to play a protumorigenic role in many cancers including www.aacrjournals.org 5623 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 2, 2019; DOI: 10.1158/1078-0432.CCR-18-2207 Dylgjeri et al. processes. Genetic and pharmacologic inhibition, using a specific Translational Relevance laboratory grade DNA-PK inhibitor (NU7441) and a clinical DNA-dependent protein kinase catalytic subunit (DNA-PK) grade dual DNA-PK/TOR kinase (DNAPK/TORK) inhibitor is a driver of aggressive disease and has been nominated as a (CC-115; refs. 22–26), led to the inhibition of proliferation in therapeutic target in multiple cancer types. Targeting DNA-PK castration-resistant prostate cancer (CRPC) models. Unbiased is an attractive therapeutic strategy that can lead to significant transcriptomic analyses demonstrated the modulation of path- anticancer effects. However, further understanding of DNA-PK ways known to be regulated by DNA-PK, including androgen functions, especially transcriptional regulation, is essential for response, estrogen signaling, cell cycle, and proliferation path- the development of effective treatments. This study demon- ways. Novel processes of cancer relevance modulated by DNA-PK, strates that DNA-PK transcriptionally modulates gene net- including oxidative phosphorylation, epithelial–mesenchymal works beyond its known function in DNA repair, hormone transition, TNFa signaling via NF-kB, TGFb signaling, and KRAS signaling, and metastatic pathways. Data herein identified signaling were also uncovered. Inhibition of DNA-PK/TORK via novel DNA-PK–mediated functions including the regulation CC-115 led to the transcriptional upregulation of androgen of epithelial–mesenchymal transition, immune response, and signaling due to TORK inhibition, which was expected on the metabolic processes. Moreover, the unbiased transcriptomic basis of previous studies. The observed upregulation of androgen data in this study informed the investigation of a combina- response upon dual DNA-PK/TORK inhibition served as a torial strategy targeting DNA-PK/TOR kinase (TORK), and rationale to test the combination with androgen receptor (AR) androgen receptor (AR), which is currently being evaluated antagonist, enzalutamide. Combinatorial treatment of DNA-PK in the clinical setting in castration-resistant prostate cancer targeting agents with enzalutamide resulted in an expansion of (CRPC). The data presented in this study have led to bench-to- the transcriptional changes and uncovered distinct downstream bed discoveries that have the potential to affect the manage- transcriptional alterations as compared with single-agent tar- ment and treatment of CRPC in the clinical setting. geting including Wnt–b-catenin signaling, Hedgehog signaling, inflammatory response, and immune response signaling. Fur- thermore, several cancer-relevant pathways regulated exclusive- ly by DNA-PK were identified by comparing the transcriptional prostate, breast, colon, cervix, and chronic leukemias (8–11). effects caused by a specific TORK inhibitor (CC-223), with the DNA-PK is upregulated as a function of disease progression in dual DNA-PK/TORK inhibitor (CC-115), both in combination prostate cancer, among other, and both DNA-PK overexpression with enzalutamide. Finally, cotargeting of DNA-PK/TORK and and hyperactivation are associated with aggressive disease (12). AR led to cooperative antiproliferative effects in vitro, in vivo, Increased DNA-PK expression and activity correlate with resis- and ex vivo in PDEs. In sum, the data herein demonstrate that in tance to both chemotherapy and radiation therapy and overall the absence of exogenous DNA damage, DNA-PK regulates poor outcomes, thus nominating DNA-PK as a potential thera- protumorigenic pathways that can be effectively targeted using peutic target in the management of cancer (8, 13). Previous clinically relevant pharmacologic agents and that DNA-PK studies in multiple tumor types, including prostate cancer, have inhibitors can act in concert with AR antagonists in advanced shown that downregulation of DNA-PK via genetic perturbation prostate cancer. or pharmacologic inhibition leads to sensitization to radiation, decreased tumor size,
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