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Cancer Res. 2015 Oct 1;75(19):4211-23. doi: 10.1158/0008-5472.CAN-15-1107. Epub 2015 Aug 21.

Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs.

Author information

1
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
2
Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
3
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
4
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. AnQual Laboratories, School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
5
Department of Otolaryngology-Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada.
6
Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
7
Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada.
8
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
9
Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
10
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
11
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Ontario Institute for Cancer Research, Toronto, Ontario, Canada. bwouters@uhnresearch.ca.

Abstract

Hypoxia is a prevalent feature of many tumors contributing to disease progression and treatment resistance, and therefore constitutes an attractive therapeutic target. Several hypoxia-activated prodrugs (HAP) have been developed, including the phase III candidate TH-302 (evofosfamide) and the preclinical agent SN30000, which is an optimized analogue of the well-studied HAP tirapazamine. Experience with this therapeutic class highlights an urgent need to identify biomarkers of HAP sensitivity, including enzymes responsible for prodrug activation during hypoxia. Using genome-scale shRNA screens and a high-representation library enriched for oxidoreductases, we identified the flavoprotein P450 (cytochrome) oxidoreductase (POR) as the predominant determinant of sensitivity to SN30000 in three different genetic backgrounds. No other genes consistently modified SN30000 sensitivity, even within a POR-negative background. Knockdown or genetic knockout of POR reduced SN30000 reductive metabolism and clonogenic cell death and similarly reduced sensitivity to TH-302 under hypoxia. A retrospective evaluation of head and neck squamous cell carcinomas showed heterogeneous POR expression and suggested a possible relationship between human papillomavirus status and HAP sensitivity. Taken together, our study identifies POR as a potential predictive biomarker of HAP sensitivity that should be explored during the clinical development of SN30000, TH-302, and other hypoxia-directed agents.

PMID:
26297733
DOI:
10.1158/0008-5472.CAN-15-1107
[Indexed for MEDLINE]
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