Oncotarget

Research Papers:

Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy

Rachel Abbotts, Rosalyn Jewell, Jérémie Nsengimana, David J. Maloney, Anton Simeonov, Claire Seedhouse, Faye Elliott, Jon Laye, Christy Walker, Ajit Jadhav, Anna Grabowska, Graham Ball, Poulam M. Patel, Julia Newton-Bishop, David M. Wilson III and Srinivasan Madhusudan _

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Oncotarget. 2014; 5:3273-3286. https://doi.org/10.18632/oncotarget.1926

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Abstract

Rachel Abbotts1, Rosalyn Jewell2, Jérémie Nsengimana2, David J Maloney3, Anton Simeonov3, Claire Seedhouse4, Faye Elliott2, Jon Laye2, Christy Walker2, Ajit Jadhav3, Anna Grabowska5, Graham Ball6, Poulam M Patel1 , Julia Newton-Bishop2, David M Wilson III7 and Srinivasan Madhusudan1

1 Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, UK.

2 Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds; Leeds, UK

3 NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.

4 Academic Haematology, Division of Oncology, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, UK.

5 Cancer Biology Unit, Division of Oncology, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, UK.

6 School of Science and Technology, Nottingham Trent University, Clifton campus Nottingham, UK

7 Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224-6825, USA.

Correspondence:

Srinivasan Madhusudan, email:

Keywords: PTEN; DNA repair; APE1; APE1 inhibitors; synthetic lethality

Received: March 14, 2014 Accepted: April 25, 2014 Published: April 27, 2014

Abstract

Phosphatase and tensin homolog (PTEN) loss is associated with genomic instability. APE1 is a key player in DNA base excision repair (BER) and an emerging drug target in cancer. We have developed small molecule inhibitors against APE1 repair nuclease activity. In the current study we explored a synthetic lethal relationship between PTEN and APE1 in melanoma. Clinicopathological significance of PTEN mRNA and APE1 mRNA expression was investigated in 191 human melanomas. Preclinically, PTEN-deficient BRAF-mutated (UACC62, HT144, and SKMel28), PTEN-proficient BRAF-wildtype (MeWo), and doxycycline-inducible PTEN-knockout BRAF-wildtype MeWo melanoma cells were DNA repair expression profiled and investigated for synthetic lethality using a panel of four prototypical APE1 inhibitors. In human tumours, low PTEN mRNA and high APE1 mRNA was significantly associated with reduced relapse free and overall survival. Pre-clinically, compared to PTEN-proficient cells, PTEN-deficient cells displayed impaired expression of genes involved in DNA double strand break (DSB) repair. Synthetic lethality in PTEN-deficient cells was evidenced by increased sensitivity, accumulation of DSBs and induction of apoptosis following treatment with APE1 inhibitors. We conclude that PTEN deficiency is not only a promising biomarker in melanoma, but can also be targeted by a synthetic lethality strategy using inhibitors of BER, such as those targeting APE1.


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