[Research Articles] Therapeutic Targeting of a Robust Non-Oncogene Addiction to PRKDC in ATM-Defective Tumors

Sci Transl Med 12 June 2013:
Vol. 5, Issue 189, p. 189ra78
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3005814 Cancer Arina Riabinska1,*, Mathias Daheim1,*, Grit S. Herter-Sprie1,†, Johannes Winkler2,3, Christian Fritz1,3, Michael Hallek1, Roman K. Thomas3,4,5, Karl-Anton Kreuzer1, Lukas P. Frenzel1,3, Parisa Monfared1, Jorge Martins-Boucas1, Shuhua Chen1,*,‡ and Hans Christian Reinhardt1,3,5,*,‡

1Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany.

2Institute for Genetics, University of Cologne, 50937 Cologne, Germany.

3Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.

4Department of Translational Genomics, University of Cologne, 50931 Cologne, Germany.

5Collaborative Research Center 832, Molecular Basis and Modulation of Cellular Interaction in the Tumor Microenvironment, 50937 Cologne, Germany. ?‡Corresponding author. E-mail: christian.reinhardt{at}uk-koeln.de (H.C.R.); shuhua.chen{at}uni-koeln.de (S.C.) ?* These authors contributed equally to this work.

?† Present address: Dana-Farber Cancer Institute, Boston, MA 02215, USA.

When the integrity of the genome is threatened, cells activate a complex, kinase-based signaling network to arrest the cell cycle, initiate DNA repair, or, if the extent of damage is beyond repair capacity, induce apoptotic cell death. The ATM protein lies at the heart of this signaling network, which is collectively referred to as the DNA damage response (DDR). ATM is involved in numerous DDR-regulated cellular responses—cell cycle arrest, DNA repair, and apoptosis. Disabling mutations in the gene encoding ATM occur frequently in various human tumors, including lung cancer and hematological malignancies. We report that ATM deficiency prevents apoptosis in human and murine cancer cells exposed to genotoxic chemotherapy. Using genetic and pharmacological approaches, we demonstrate in vitro and in vivo that ATM-defective cells display strong non-oncogene addiction to DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Further, this dependence of ATM-defective cells on DNA-PKcs offers a window of opportunity for therapeutic intervention: We show that pharmacological or genetic abrogation of DNA-PKcs in ATM-defective cells leads to the accumulation of DNA double-strand breaks and the subsequent CtBP-interacting protein (CtIP)–dependent generation of large single-stranded DNA (ssDNA) repair intermediates. These ssDNA structures trigger proapoptotic signaling through the RPA/ATRIP/ATR/Chk1/p53/Puma axis, ultimately leading to the apoptotic demise of ATM-defective cells exposed to DNA-PKcs inhibitors. Finally, we demonstrate that DNA-PKcs inhibitors are effective as single agents against ATM-defective lymphomas in vivo. Together, our data implicate DNA-PKcs as a drug target for the treatment of ATM-defective malignancies.

Copyright © 2013, American Association for the Advancement of ScienceCitation: A. Riabinska, M. Daheim, G. S. Herter-Sprie, J. Winkler, C. Fritz, M. Hallek, R. K. Thomas, K.-A. Kreuzer, L. P. Frenzel, P. Monfared, J. Martins-Boucas, S. Chen, H. C. Reinhardt, Therapeutic Targeting of a Robust Non-Oncogene Addiction to PRKDC in ATM-Defective Tumors. Sci. Transl. Med. 5, 189ra78 (2013).

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