Pleiotropic impact of DNA-PK in cancer and implications for therapeutic strategies

Emanuela Dylgjeri, Christopher McNair, Jonathan F. Goodwin, Heather K. Raymon, Peter A. McCue, Ayesha A. Shafi, Benjamin E. Leiby, Renee De Leeuw, Vishal Kothari, Jennifer J. McCann, Amy C. Mandigo, Saswati N. Chand, Matthew J. Schiewer, Lucas J. Brand, Irina Vasilevskaya, Nicolas Gordon, Talya S. Laufer, Leonard G. Gomella, Costas D. Lallas, Edouard J. TrabulsiFelix Y. Feng, Ellen H. Filvaroff, Kristin Hege, Dana Rathkopf, Karen E. Knudsen*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Purpose: DNA-dependent protein kinase catalytic subunit (DNA-PK) is a pleiotropic kinase involved in DNA repair and transcriptional regulation. DNA-PK is deregulated in selected cancer types and is strongly associated with poor outcome. The underlying mechanisms by which DNA-PK promotes aggressive tumor phenotypes are not well understood. Here, unbiased molecular investigation in clinically relevant tumor models reveals novel functions of DNA-PK in cancer. Experimental Design: DNA-PK function was modulated using both genetic and pharmacologic methods in a series of in vitro models, in vivo xenografts, and patient-derived explants (PDE), and the impact on the downstream signaling and cellular cancer phenotypes was discerned. Data obtained were used to develop novel strategies for combinatorial targeting of DNA-PK and hormone signaling pathways. Results: Key findings reveal that (i) DNA-PK regulates tumor cell proliferation; (ii) pharmacologic targeting of DNA-PK suppresses tumor growth both in vitro, in vivo, and ex vivo; (iii) DNA-PK transcriptionally regulates the known DNA-PK-mediated functions as well as novel cancer-related pathways that promote tumor growth; (iv) dual targeting of DNA-PK/TOR kinase (TORK) transcriptionally upregulates androgen signaling, which can be mitigated using the androgen receptor (AR) antagonist enzalutamide; (v) cotargeting AR and DNA-PK/TORK leads to the expansion of antitumor effects, uncovering the modulation of novel, highly relevant protumorigenic cancer pathways; and (viii) cotargeting DNA-PK/TORK and AR has cooperative growth inhibitory effects in vitro and in vivo. Conclusions: These findings uncovered novel DNA-PK transcriptional regulatory functions and led to the development of a combinatorial therapeutic strategy for patients with advanced prostate cancer, currently being tested in the clinical setting.

Original languageEnglish (US)
Pages (from-to)5623-5638
Number of pages16
JournalClinical Cancer Research
Volume25
Issue number18
DOIs
StatePublished - Sep 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Dylgjeri, E., McNair, C., Goodwin, J. F., Raymon, H. K., McCue, P. A., Shafi, A. A., Leiby, B. E., De Leeuw, R., Kothari, V., McCann, J. J., Mandigo, A. C., Chand, S. N., Schiewer, M. J., Brand, L. J., Vasilevskaya, I., Gordon, N., Laufer, T. S., Gomella, L. G., Lallas, C. D., ... Knudsen, K. E. (2019). Pleiotropic impact of DNA-PK in cancer and implications for therapeutic strategies. Clinical Cancer Research, 25(18), 5623-5638. https://doi.org/10.1158/1078-0432.CCR-18-2207