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.
Highlights
Phosphatase and tensin homolog (PTEN) is a tumor suppressor known to negatively regulate the phosphoinositide 3-kinase (PI3K)/AKT signaling axis in order to control cell cycle progression, growth, and survival [1]
We report that 3E10 affects cellular viability of PTEN deficient cells in both glioma cell lines and in patient-derived primary melanoma cultures, indicating that inhibiting homology dependent repair (HDR) with 3E10 leads to cytotoxicity in PTEN deficient cells
Based on prior work suggesting that PTEN loss causes a reduction in nonhomologous end-joining (NHEJ), the other major cellular pathway of DNA double strand break (DSB) repair [18], we sought to test the effect of the 3E10 on PTEN deficient cells
Summary
Phosphatase and tensin homolog (PTEN) is a tumor suppressor known to negatively regulate the phosphoinositide 3-kinase (PI3K)/AKT signaling axis in order to control cell cycle progression, growth, and survival [1]. Loss of PTEN is often associated with higher grade tumors and shorter progression free and overall survival [9, 10]. PTEN loss has been associated with chromosomal instability, sensitivity to DNA damaging agents, and compromised genomic integrity [11,12,13,14,15]. Many publications have linked PTEN to DNA double strand break (DSB) repair [13, 16,17,18]. DNA double-strand breaks (DSBs) are the most deleterious form of DNA damage, but DSBs are repaired by two main pathways: non-homologous end-joining (NHEJ) and homologydirected repair (HDR). PTEN has been implicated to play a role in both HDR and NHEJ, but recently, our group has reported that PTEN promotes NHEJ by epigenetically inducing XLF gene expression [18], such that PTEN null cells show reduced XLF expression and diminished NHEJ efficiency
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