Synthetic lethality of a cell-penetrating anti-RAD51 antibody in PTEN-deficient melanoma and glioma cells
Year: 2019
Type: article
Abstract: // Audrey Turchick 1 , Yanfeng Liu 2 , Weixi Zhao 2 , Inessa Cohen 2 and Peter M. Glazer 1,2 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: [email protected] 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.
Source: Oncotarget
Institution: Yale University
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
Funders: Yale University, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W2914397291