Abbotts, R, Jewell, R, Nsengimana, J et al. (13 more authors) (2014) Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy. Oncotarget, 5 (10). pp. 3273-3286. ISSN 1949-2553
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2014, The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
Keywords: | Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Line, Tumor; Comet Assay; DNA-(Apurinic or Apyrimidinic Site) Lyase; Flow Cytometry; Gene Knockdown Techniques; Genome-Wide Association Study; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Melanoma; Molecular Targeted Therapy; PTEN Phosphohydrolase; RNA, Messenger; Real-Time Polymerase Chain Reaction; Transfection |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Epidemiology and Biostatistics (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 24 Mar 2017 15:43 |
Last Modified: | 24 Mar 2017 15:43 |
Published Version: | https://doi.org/10.18632/oncotarget.1926 |
Status: | Published |
Publisher: | Impact Journals |
Identification Number: | 10.18632/oncotarget.1926 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:111010 |