title: Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Clinical Sciences, and Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center; and VA North Texas Health Care System, Dallas, Texas.
authors.forename: Carlos Rodrigo
authors.initials: CR
authors.lastname: Gil del Alcazar
authors.forename: Molly Catherine
authors.initials: MC
authors.lastname: Hardebeck
authors.forename: Bipasha
authors.initials: B
authors.lastname: Mukherjee
authors.forename: Nozomi
authors.initials: N
authors.lastname: Tomimatsu
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Gao
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Yan
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.forename: Robert
authors.initials: R
authors.lastname: Bachoo
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Amyn A
authors.initials: AA
authors.lastname: Habib
authors.forename: Sandeep
authors.initials: S
authors.lastname: Burma
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077204:Temozolomide
chemical_list: D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D011838:Radiation-Sensitizing Agents; D003606:Dacarbazine; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib; D000077204:Temozolomide