Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors

The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
EMBO Molecular Medicine (Impact Factor: 8.25). 09/2009; 1(6-7):315-22. DOI: 10.1002/emmm.200900041
Source: PubMed

ABSTRACT The tumour suppressor gene, phosphatase and tensin homolog (PTEN), is one of the most commonly mutated genes in human cancers. Recent evidence suggests that PTEN is important for the maintenance of genome stability. Here, we show that PTEN deficiency causes a homologous recombination (HR) defect in human tumour cells. The HR deficiency caused by PTEN deficiency, sensitizes tumour cells to potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), both in vitro and in vivo. PARP inhibitors are now showing considerable promise in the clinic, specifically in patients with mutations in either of the breast cancer susceptibility genes BRCA1 or BRCA2. The data we present here now suggests that the clinical assessment of PARP inhibitors should be extended beyond those with BRCA mutations to a larger group of patients with PTEN mutant tumours.

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Available from: Ana M Mendes-Pereira, Jul 28, 2015
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    • "PTEN/PI3K pathway activation may be a strong biological correlate of metastasis and poor prognosis in some tumors [5] [6] [7]. Moreover, a new functional role for PTEN in genomic instability has been proposed [4] suggesting that PARP (poly ADP ribose polymerase) inhibitors may be useful in patients with PTEN mutant tumors [8]. Furthermore, PTEN expression has also been related to response to several drugs in anticancer targeted therapies [9] [10] [11]. "
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    ABSTRACT: In some tumors, phosphatase and tensin homolog (PTEN) inactivation may have prognostic importance and predictive value for targeted therapies. Immunohistochemistry (IHC) may be an effective method to demonstrate PTEN loss. It was claimed that PTEN IHC showed poor reproducibility, lack of standardization, and variable effects of preanalytical factors. In this study, we developed an optimal protocol for PTEN IHC, with clone 6H2.1, by checking the relevance of analytical variables in normal tissue and tumors of endometrium, breast, and prostate. Pattern and intensity of cellular staining and background nonspecific staining were quantified and subjected to statistical analysis by linear mixed models. The proposed protocol showed a statistically best performance (P < .05) and included a high target retrieval solution, 1:100 primary antibody dilution (2.925 mg/L), FLEX diluent, and EnVisionFLEX+ detection method, with a sensitivity and specificity of 72.33% and 78.57%, respectively. Staining specificity was confirmed in cell lines and animal models. Endometrial carcinomas with PTEN genetic abnormalities showed statistically lower staining than tumors without alterations (mean histoscores, 34.66 and 119.28, respectively; P = .01). Controlled preanalytical factors (delayed fixation and overfixation) did not show any statistically significant effect on staining with optimal protocol (P > .001). However, there was a trend of significance for decreased staining and fixation under high temperature. Moreover, staining was better in endometrial aspirates than in matched hysterectomy specimens, subjected to less controlled preanalytical variables (mean histoscores, 80 and 40, respectively; P = .002). A scoring system combining intensity of staining and percentage of positive cells was statistically associated with PTEN alterations (P = .01).
    Human pathology 11/2013; 45(3). DOI:10.1016/j.humpath.2013.10.018 · 2.81 Impact Factor
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    • "Loss of PTEN leads to AKTmediated phosphorylation and cytoplasmic sequestration of the cell cycle regulator checkpoint kinase 1 (CHEK1), disrupting the G2-M cell cycle checkpoint and leading to DNA double-strand breaks (Puc et al., 2005). In support of a role of PTEN in the maintenance of genome stability, PTEN loss was shown to cause homologous recombination defects in human tumor cells, sensitizing them to inhibitors of poly(ADP-ribose) polymerase (PARP) (Mendes-Pereira et al., 2009). "
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    ABSTRACT: Breast cancer is the most common type of cancer in women. A substantial fraction of breast cancers have acquired mutations that lead to activation of the phosphoinositide 3-kinase (PI3K) signaling pathway, which plays a central role in cellular processes that are essential in cancer, such as cell survival, growth, division and motility. Oncogenic mutations in the PI3K pathway generally involve either activating mutation of the gene encoding PI3K (PIK3CA) or AKT (AKT1), or loss or reduced expression of PTEN. Several kinases involved in PI3K signaling are being explored as a therapeutic targets for pharmacological inhibition. Despite the availability of a range of inhibitors, acquired resistance may limit the efficacy of single-agent therapy. In this review we discuss the role of PI3K pathway mutations in human breast cancer and relevant genetically engineered mouse models (GEMMs), with special attention to the role of PI3K signaling in oncogenesis, in therapeutic response, and in resistance to therapy. Several sophisticated GEMMs have revealed the cause-and-effect relationships between PI3K pathway mutations and mammary oncogenesis. These GEMMs enable us to study the biology of tumors induced by activated PI3K signaling, as well as preclinical response and resistance to PI3K pathway inhibitors.
    Molecular oncology 02/2013; 7(2). DOI:10.1016/j.molonc.2013.02.003 · 5.94 Impact Factor
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    • "Although this synthetic lethal approach seems to be a promising therapy, BRCA mutation is rarely reported in GBM (Parsons et al., 2008; TCGA, 2008). However, it has recently been reported that mutation of tumor suppressor PTEN is linked to impairment of a HR repair pathway, implicating synthetic lethal targeting of PTEN mutant cells with PARP inhibitors (Shen et al., 2007; Mendes-Pereira et al., 2009; McEllin et al., 2010; Ming and He, 2012). Given that PTEN mutation is identified in about one-third of GBM patients (Parsons et al., 2008; TCGA, 2008), PARP inhibitor monotherapy has the potential to be an effective treatment strategy for the PTEN-mutated GBM. "
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    ABSTRACT: Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ) is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma (GBM). Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of GBM to TMZ, a subset of GBM does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR), and the base excision repair (BER) pathway in the mechanism of mediating TMZ resistance, but emerging roles for the DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break repair and double-strand break repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance in the clinic.
    Frontiers in Oncology 12/2012; 2:186. DOI:10.3389/fonc.2012.00186
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