Abstract 3745: The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKcs-mediated DNA damage responses

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Neoplasia (New York, N.Y.) (Impact Factor: 4.25). 06/2012; 14(1):34-43. DOI: 10.1158/1538-7445.AM2012-3745
Source: PubMed

ABSTRACT Inhibitors of PI3K/Akt signaling are being actively developed for tumor therapy owing to the frequent mutational activation of the PI3K-Akt-mTORC1 pathway in many cancers, including glioblastomas (GBMs). NVP-BEZ235 is a novel and potent dual PI3K/mTOR inhibitor that is currently in phase 1/2 clinical trials for advanced solid tumors. Here, we show that NVP-BEZ235 also potently inhibits ATM and DNA-PKcs, the two major kinases responding to ionizing radiation (IR)-induced DNA double-strand breaks (DSBs). Consequently, NVP-BEZ235 blocks both nonhomologous end joining and homologous recombination DNA repair pathways resulting in significant attenuation of DSB repair. In addition, phosphorylation of ATMtargets and implementation of the G(2)/M cell cycle checkpoint are also attenuated by this drug. As a result, NVP-BEZ235 confers an extreme degree of radiosensitization and impairs DSB repair in a panel of GBM cell lines irrespective of their Akt activation status. NVP-BEZ235 also significantly impairs DSB repair in a mouse tumor model thereby validating the efficacy of this drug as a DNA repair inhibitor in vivo. Our results, showing that NVP-BEZ235 is a potent and novel inhibitor of ATM and DNA-PKcs, have important implications for the informed and rational design of clinical trials involving this drug and also reveal the potential utility of NVP-BEZ235 as an effective radiosensitizer for GBMs in the clinic.

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Available from: Cristel V Camacho, Mar 04, 2014
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    • "However it is more difficult to determine to what extent alleviation of hypoxia accounts for these results, because these inhibitors also sensitize cells to DNA damage under oxic conditions. Inhibition of PI3K reduces DNA damage repair, but BEZ235 also has off-target effects of inhibition of ATR and DNA-PK [29]. Fokas et al. attempted to separate the effects on tumor oxygenation from cell-specific effects by administering the drug BEZ235 immediately before tumor radiation, when it still altered tumor signaling but before the more prolonged changes of hypoxia associated with extended preincubation had occurred. "
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    ABSTRACT: Background Inhibitors of the phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathway are currently in clinical trials. In addition to antiproliferative and proapoptotic effects, these agents also diminish tumor hypoxia. Since hypoxia is a major cause of resistance to radiotherapy, we sought to understand how it is regulated by PI3K/mTOR inhibition. Methods Whole cell, mitochondrial, coupled and uncoupled oxygen consumption were measured in cancer cells after inhibition of PI3K (Class I) and mTOR by pharmacological means or by RNAi. Mitochondrial composition was assessed by immunoblotting. Hypoxia was measured in spheroids, in tumor xenografts and predicted with mathematical modeling. Results Inhibition of PI3K and mTOR reduced oxygen consumption by cancer cell lines is predominantly due to reduction of mitochondrial respiration coupled to ATP production. Hypoxia in tumor spheroids was reduced, but returned after removal of the drug. Murine tumors had increased oxygenation even in the absence of average perfusion changes or tumor necrosis. Conclusions Targeting the PI3K/mTOR pathway substantially reduces mitochondrial oxygen consumption thereby reducing tumor hypoxia. These alterations in tumor hypoxia should be considered in the design of clinical trials using PI3K/mTOR inhibitors, particularly in conjunction with radiotherapy.
    Radiotherapy and Oncology 04/2014; 111(1). DOI:10.1016/j.radonc.2014.02.007 · 4.36 Impact Factor
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    • "BEZ235 has been shown to radiosensitize tumors of various tissues, including glioblastomas, fibrosarcomas, and NCSLC cell lines harboring K-RAS mutations [36–38]. BEZ235 also normalizes tumor vasculature in xenograft experiments, leading to improved tumor perfusion, oxygenation, and responses to radiotherapy [36]. "
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    ABSTRACT: Approximately 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with poor clinical response to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs) that synergize with ionizing radiation (IR) ("radiosensitizers") that could be incorporated into current treatment strategies for locally advanced rectal cancers (LARCs) expressing mutant K-RAS. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5-fluorouracil (5-FU), which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC.
    PLoS ONE 12/2013; 8(12):e82982. DOI:10.1371/journal.pone.0082982 · 3.23 Impact Factor
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    • "Recently, NVP-BEZ235 also emerged as inhibitor of ATM and DNA-PK at low concentration (100 nM). In this context, treatment with NVP-BEZ235 may have significant radio sensitizing effects with important implications in the rational design of clinical trials (Mukherjee et al., 2012). At present, this molecule is under evaluation in phase I/II clinical trials in patients with advanced solid malignancies, including GBM (Salkeni et al., 2012), breast, renal cell carcinoma (RCC), castration-resistant prostate cancer (CRPC), endometrial carcinoma, and pancreatic neuroendocrine tumors (see text footnote 2), alone or in combination with other drugs such as Paclitaxel, Trastuzumab, Everolimus, and MEK162. "
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    ABSTRACT: The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates several cellular processes and it's one of the most frequently deregulated pathway in human tumors. Given its prominent role in cancer, there is great interest in the development of inhibitors able to target several members of PI3K signaling pathway in clinical trials. These drug candidates include PI3K inhibitors, both pan- and isoform-specific inhibitors, AKT, mTOR, and dual PI3K/mTOR inhibitors. As novel compounds progress into clinical trials, it's becoming urgent to identify and select patient population that most likely benefit from PI3K inhibition. In this review we will discuss individual PIK3CA mutations as predictors of sensitivity and resistance to targeted therapies, leading to use of novel PI3K/mTOR/AKT inhibitors to a more "personalized" treatment.
    Frontiers in Oncology 05/2013; 3:108. DOI:10.3389/fonc.2013.00108
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