TY - JOUR
T1 - Pleiotropic impact of DNA-PK in cancer and implications for therapeutic strategies
AU - Dylgjeri, Emanuela
AU - McNair, Christopher
AU - Goodwin, Jonathan F.
AU - Raymon, Heather K.
AU - McCue, Peter A.
AU - Shafi, Ayesha A.
AU - Leiby, Benjamin E.
AU - De Leeuw, Renee
AU - Kothari, Vishal
AU - McCann, Jennifer J.
AU - Mandigo, Amy C.
AU - Chand, Saswati N.
AU - Schiewer, Matthew J.
AU - Brand, Lucas J.
AU - Vasilevskaya, Irina
AU - Gordon, Nicolas
AU - Laufer, Talya S.
AU - Gomella, Leonard G.
AU - Lallas, Costas D.
AU - Trabulsi, Edouard J.
AU - Feng, Felix Y.
AU - Filvaroff, Ellen H.
AU - Hege, Kristin
AU - Rathkopf, Dana
AU - Knudsen, Karen E.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/9/15
Y1 - 2019/9/15
N2 - 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.
AB - 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.
KW - Androgen Receptor Antagonists/pharmacology
KW - Animals
KW - Antineoplastic Agents/pharmacology
KW - Biomarkers, Tumor
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - DNA-Activated Protein Kinase/antagonists & inhibitors
KW - Disease Models, Animal
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Humans
KW - Male
KW - Mice
KW - Molecular Targeted Therapy
KW - Neoplasms/drug therapy
KW - Protein Kinase Inhibitors/pharmacology
KW - Receptors, Androgen/metabolism
KW - TOR Serine-Threonine Kinases/metabolism
KW - Transcription, Genetic
KW - Xenograft Model Antitumor Assays
UR - http://www.scopus.com/inward/record.url?scp=85071266794&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000487704400022&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1158/1078-0432.CCR-18-2207
DO - 10.1158/1078-0432.CCR-18-2207
M3 - Article
C2 - 31266833
SN - 1078-0432
VL - 25
SP - 5623
EP - 5637
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -