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Author Notes:

Correspondence: Philip W. Kantoff, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA, Tel: 212-639-5851, Fax: 929-321-5023, kantoff@mskcc.org

Author contributions: Conception and design: Y.Z. Mazzu, P.W. Kantoff. Development of methodology: Y.Z. Mazzu.

Acquisition of data (provided animals, acquired and managed patient cohort data, provided facilities, etc.): Y.Z. Mazzu, J. Armenia, G. Chakraborty, Y. Yoshikawa, S.A. Coggins, S. Nandakumar, T.A. Gerke, M.M. Pomerantz, X. Qiu, H. Zhao, M. Atiq, N. Khan, K. Komura, G.M. Lee, S.W. Fine, C. Bell, E. O’Connor, H.W. Long, M.L. Freedman, B. Kim, P.W. Kantoff

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Y.Z. Mazzu, J. Armenia, S. Nandakumar, T.A. Gerke, M.M. Pomerantz, P.W. Kantoff. Writing, review, and/or revision of the manuscript: Y.Z. Mazzu, J. Armenia, S. Nandakumar, M.M. Pomerantz, P.W. Kantoff.

Administrative, technical, or material support (i.e., reporting or organizing data): Y.Z. Mazzu, J. Armenia, G. Chakraborty, Y. Yoshikawa, S.A. Coggins, S. Nandakumar, M.M. Pomerantz. Study supervision: P.W. Kantoff.

Disclosures: As of February 18, 2019, P.W. Kantoff reports the following disclosures for the last 36-month period: he has investment interest in Context Therapeutics LLC, DRGT, Placon, Seer Biosciences, and Tarveda Therapeutics; he is a company board member for Context Therapeutics LLC; he is a consultant/scientific advisory board member for BIND Biosciences, Inc.,

Bavarian Nordic Immunotherapeutics, DRGT, GE Healthcare, Janssen, Metamark, New England Research Institutes, Inc., OncoCellMDX, Progenity, Sanofi, Seer Biosciences, Tarveda Therapeutics, and Thermo Fisher; and he serves on data safety monitoring boards for Genentech/Roche and Merck.

J. Armenia is currently an employee of AstraZeneca, but was not when he performed this work. All other authors declare no potential conflicts of interest.

Subjects:

Research Funding:

This research was funded in part through the NIH/NCI Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748) and dNTP assays were funded in part through NIH/NIGMS R01 GM104198 to B. Kim and NIH/NIAID R01 AI136581 to B. Kim.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Enrichment analysis
  • Expression
  • Signature
  • Degradation
  • Progression
  • Tumors
  • Cells

A Novel Mechanism Driving Poor-Prognosis Prostate Cancer: Overexpression of the DNA Repair Gene, Ribonucleotide Reductase Small Subunit M2 (RRM2)

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Journal Title:

Clinical Cancer Research

Volume:

Volume 25, Number 14

Publisher:

, Pages 4480-4492

Type of Work:

Article | Post-print: After Peer Review

Abstract:

PURPOSE: Defects in genes in the DNA-repair pathways significantly contribute to prostate cancer (PC) progression. We hypothesize that overexpression of DNA repair genes may also drive poorer outcomes in PC. The ribonucleotide reductase small subunit M2 (RRM2) is essential for DNA synthesis and DNA repair by producing dNTPs. It is frequently overexpressed in cancers, but there is very little known about its function in PC. EXPERIMENTAL DESIGN: The oncogenic activity of RRM2 in PC cells was assessed by inhibiting or overexpressing RRM2. The molecular mechanisms of RRM2 function were determined. The clinical significance of RRM2 overexpression was evaluated in 11 PC clinical cohorts. The efficacy of an RRM2 inhibitor (COH29) was assessed in vitro and in vivo. Last, the mechanism underlying the transcriptional activation of RRM2 in PC tissue and cells was determined. RESULTS: Knockdown of RRM2 inhibited its oncogenic function, while overexpression of RRM2 promoted epithelial mesenchymal transition in PC cells. The prognostic value of RRM2 RNA levels in PC was confirmed in 11 clinical cohorts. Integrating the transcriptomic and phospho-proteomic changes induced by RRM2 unraveled multiple oncogenic pathways downstream of RRM2. Targeting RRM2 with COH29 showed excellent efficacy. Thirteen putative RRM2-targeting transcription factors were bioinformatically identified, and FOXM1 was validated to transcriptionally activate RRM2 in PC. CONCLUSIONS: We propose that increased expression of RRM2 is a mechanism driving poor patient outcomes in PC and that its inhibition may be of significant therapeutic value.

Copyright information:

© 2019 American Association for Cancer Research.

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