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      Acquired resistance to tyrosine kinase inhibitors may be linked with the decreased sensitivity to X-ray irradiation

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          Abstract

          Acquired resistance to chemotherapy and radiation therapy is one of the major obstacles decreasing efficiency of treatment of the oncologic diseases. In this study, on the two cell lines (ovarian carcinoma SKOV-3 and neuroblastoma NGP-127), we modeled acquired resistance to five target anticancer drugs. The cells were grown on gradually increasing concentrations of the clinically relevant tyrosine kinase inhibitors (TKIs) Sorafenib, Pazopanib and Sunitinib, and rapalogs Everolimus and Temsirolimus, for 20 weeks. After 20 weeks of culturing, the half-inhibitory concentrations (IC 50) increased by 25 – 186% for the particular combinations of the drugs and cell types. We next subjected cells to 10 Gy irradiation, a dose frequently used in clinical radiation therapy. For the SKOV-3, but not NGP-127 cells, for the TKIs Sorafenib, Pazopanib and Sunitinib, we noticed statistically significant increase in capacity to repair radiation-induced DNA double strand breaks compared to naïve control cells not previously treated with TKIs. These peculiarities were linked with the increased activation of ATM DNA repair pathway in the TKI-treated SKOV-3, but not NGP-127 cells. Our results provide a new cell culture model for studying anti-cancer therapy efficiency and evidence that there may be a tissue-specific radioresistance emerging as a side effect of treatment with TKIs.

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          Ionizing radiation-induced DNA damage, response, and repair.

          Ionizing radiation (IR) is an effective and commonly employed treatment in the management of more than half of human malignancies. Because IR's ability to control tumors mainly relies on DNA damage, the cell's DNA damage response and repair (DRR) processes may hold the key to determining tumor responses. IR-induced DNA damage activates a number of DRR signaling cascades that control cell cycle arrest, DNA repair, and the cell's fate. DNA double-strand breaks (DSBs) generated by IR are the most lethal form of damage, and are mainly repaired via either homologous recombination (HR) or nonhomologous end-joining (NHEJ) pathways.
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            Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma.

            Inhibitors of the DNA damage response (DDR) have great potential for radiosensitization of numerous cancers, including glioblastomas, which are extremely radio- and chemoresistant brain tumors. Currently, there are no DNA double-strand break (DSB) repair inhibitors that have been successful in treating glioblastoma. Our laboratory previously demonstrated that the dual phosphoinositide 3-kinase/mTOR inhibitor NVP-BEZ235 can potently inhibit the two central DDR kinases, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia-telangiectasia mutated (ATM), in vitro. Here, we tested whether NVP-BEZ235 could also inhibit ATM and DNA-PKcs in tumors in vivo and assessed its potential as a radio- and chemosensitizer in preclinical mouse glioblastoma models. The radiosensitizing effect of NVP-BEZ235 was tested by following tumor growth in subcutaneous and orthotopic glioblastoma models. Tumors were generated using the radioresistant U87-vIII glioma cell line and GBM9 neurospheres in nude mice. These tumors were then treated with ionizing radiation and/or NVP-BEZ235 and analyzed for DNA-PKcs and ATM activation, DSB repair inhibition, and attenuation of growth. NVP-BEZ235 potently inhibited both DNA-PKcs and ATM kinases and attenuated the repair of ionizing radiation-induced DNA damage in tumors. This resulted in striking tumor radiosensitization, which extended the survival of brain tumor-bearing mice. Notably, tumors displayed a higher DSB-load when compared with normal brain tissue. NVP-BEZ235 also sensitized a subset of subcutaneous tumors to temozolomide, a drug routinely used concurrently with ionizing radiation for the treatment of glioblastoma. These results demonstrate that it may be possible to significantly improve glioblastoma therapy by combining ionizing radiation with potent and bioavailable DNA repair inhibitors such as NVP-BEZ235. ©2013 AACR
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              Residual γH2AX foci as an indication of lethal DNA lesions

              Background Evidence suggests that tumor cells exposed to some DNA damaging agents are more likely to die if they retain microscopically visible γH2AX foci that are known to mark sites of double-strand breaks. This appears to be true even after exposure to the alkylating agent MNNG that does not cause direct double-strand breaks but does produce γH2AX foci when damaged DNA undergoes replication. Methods To examine this predictive ability further, SiHa human cervical carcinoma cells were exposed to 8 DNA damaging drugs (camptothecin, cisplatin, doxorubicin, etoposide, hydrogen peroxide, MNNG, temozolomide, and tirapazamine) and the fraction of cells that retained γH2AX foci 24 hours after a 30 or 60 min treatment was compared with the fraction of cells that lost clonogenicity. To determine if cells with residual repair foci are the cells that die, SiHa cervical cancer cells were stably transfected with a RAD51-GFP construct and live cell analysis was used to follow the fate of irradiated cells with RAD51-GFP foci. Results For all drugs regardless of their mechanism of interaction with DNA, close to a 1:1 correlation was observed between clonogenic surviving fraction and the fraction of cells that retained γH2AX foci 24 hours after treatment. Initial studies established that the fraction of cells that retained RAD51 foci after irradiation was similar to the fraction of cells that retained γH2AX foci and subsequently lost clonogenicity. Tracking individual irradiated live cells confirmed that SiHa cells with RAD51-GFP foci 24 hours after irradiation were more likely to die. Conclusion Retention of DNA damage-induced γH2AX foci appears to be indicative of lethal DNA damage so that it may be possible to predict tumor cell killing by a wide variety of DNA damaging agents simply by scoring the fraction of cells that retain γH2AX foci.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                12 January 2018
                27 December 2017
                : 9
                : 4
                : 5111-5124
                Affiliations
                1 D. Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117198, Russia
                2 National Research Centre “Kurchatov Institute”, Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow 123182, Russia
                3 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia
                4 State Research Center-Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow 123098, Russia
                5 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
                6 Orekhovich Institute of Biomedical Chemistry, Moscow 119121, Russia
                7 OmicsWay Corp., Walnut, CA 91789, USA
                8 Clinical Center Vitamed, Moscow 121309, Russia
                9 Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada
                10 Department of Reproductive Medicine and Surgery, Moscow State University of Medicine and Dentistry, Moscow 127206, Russia
                11 Pathology Department, Morozov Children's City Hospital, Moscow 119049, Russia
                12 LLC “Solixant”, Moscow 119991, Russia
                13 Republic Oncological Hospital, Petrozavodsk 185000, Russia
                Author notes
                Correspondence to: Anton Buzdin, buzdin@ 123456oncobox.com
                Article
                23700
                10.18632/oncotarget.23700
                5797037
                29435166
                691e1423-14c3-4147-9c77-56dee6a6a269
                Copyright: © 2018 Sorokin et al.

                This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 5 June 2017
                : 11 December 2017
                Categories
                Research Paper

                Oncology & Radiotherapy
                tyrosine kinase,serine and threonine kinase,x-ray irradiation,drug resistance,dna repair

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