Oncotarget

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Synthetic lethality of a cell-penetrating anti-RAD51 antibody in PTEN-deficient melanoma and glioma cells

Audrey Turchick, Yanfeng Liu, Weixi Zhao, Inessa Cohen and Peter M. Glazer _

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Oncotarget. 2019; 10:1272-1283. https://doi.org/10.18632/oncotarget.26654

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Abstract

Audrey Turchick1, Yanfeng Liu2, Weixi Zhao2, Inessa Cohen2 and Peter M. Glazer1,2

1 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

2 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA

Correspondence to:

Peter M. Glazer, email: peter.glazer@yale.edu

Keywords: DNA repair; PTEN; RAD51; ATR; 3E10

Received: December 17, 2018    Accepted: January 09, 2019    Published: February 12, 2019

Abstract

PTEN is a tumor suppressor that is highly mutated in a variety of human cancers. Recent studies have suggested a link between PTEN loss and deficiency in the non-homologous end-joining (NHEJ) pathway of DNA double strand break (DSB) repair. As a means to achieve synthetic lethality in this context, we tested the effect of 3E10, a cell-penetrating autoantibody that inhibits RAD51, a key factor in the alternative pathway of DSB repair, homology dependent repair (HDR). We report here that treatment of PTEN-deficient glioma cells with 3E10 leads to an accumulation of DNA damage causing decreased proliferation and increased cell death compared to isogenic PTEN proficient controls. Similarly, 3E10 was synthetically lethal to a series of PTEN-deficient, patient-derived primary melanoma cell populations. Further, 3E10 was found to synergize with a small molecule inhibitor of the ataxia telangiectasia and Rad3-related (ATR) protein, a DNA damage checkpoint kinase, in both PTEN-deficient glioma cells and primary melanoma cells. These results point to a targeted synthetic lethal strategy to treat PTEN-deficient cancers through a combination designed to disrupt both DNA repair and DNA damage checkpoint signaling.


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