Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma

Clinical Cancer Research

Volumn 20, Issue 5, 2014, Pages 1235-1248

  Gil Del Alcazar, Carlos Rodrigo ^a   Hardebeck, Molly Catherine ^a   Mukherjee, Bipasha ^a   Tomimatsu, Nozomi ^a   Gao, Xiaohuan ^a   Yan, Jingsheng ^b   Xie, Xian Jin ^b   Bachoo, Robert ^a   Li, Li ^a,c   Habib, Amyn A ^a,c   Burma, Sandeep ^a  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^c VA NORTH TEXAS HEALTH CARE SYSTEM   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ATM PROTEIN; DACTOLISIB; DNA DEPENDENT PROTEIN KINASE; DOUBLE STRANDED DNA; TEMOZOLOMIDE;

ARTICLE; CANCER CELL CULTURE; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CANCER RADIOTHERAPY; CANCER SURVIVAL; DNA REPAIR; DOUBLE STRANDED DNA BREAK; DRUG POTENCY; ENZYME INHIBITION; GLIOBLASTOMA; GLIOMA CELL; HUMAN; IN VIVO STUDY; IONIZING RADIATION; PRIORITY JOURNAL; RADIOSENSITIZATION;

ANIMALS; ATAXIA TELANGIECTASIA MUTATED PROTEINS; BLOOD-BRAIN BARRIER; CATALYTIC DOMAIN; CELL LINE, TUMOR; DACARBAZINE; DISEASE MODELS, ANIMAL; DNA BREAKS, DOUBLE-STRANDED; DNA REPAIR; DNA-ACTIVATED PROTEIN KINASE; GLIOBLASTOMA; HUMANS; IMIDAZOLES; MICE; MICE, TRANSGENIC; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN INTERACTION DOMAINS AND MOTIFS; QUINOLINES; RADIATION-SENSITIZING AGENTS; TOR SERINE-THREONINE KINASES;

EID: 84895807281     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-13-1607     Document Type: Article

References (50)

1. Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev 2012;26:756-84.
2. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66.
3. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
4. Bao S,WuQ,McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444:756-60.
5. Li Z, Wang H, Eyler CE, Rich JN. Turning cancer stem cells inside-out: an exploration of glioma stem cell signaling pathways. J Biol Chem 2009;284:16705-9.
6. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature 2009;461:1071-8.
7. Begg AC, Stewart FA, Vens C. Strategies to improve radiotherapy with targeted drugs. Nat Rev 2011;11:239-53.
8. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA.DNA repair pathways as targets for cancer therapy. Nat Rev 2008;8:193-204.
9. Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature 2012;481:287-94.
10. Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 2013; 14:197-210.
11. Wang C, Lees-Miller SP. Detection and repair of ionizing radiationinduced DNA double strand breaks: new developments in nonhomologous end joining. Int J Radiation Oncol Biol Phys 2013;86:440-9.
12. Finlay MR, Griffin RJ. Modulation of DNA repair by pharmacological inhibitors of the PIKK protein kinase family. Bioorg Med Chem Lett 2012;22:5352-9.
13. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008;7:1851-63.
14. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 2008;27:5511-26.
15. Mukherjee B, Tomimatsu N, Amancherla K, Camacho CV, Pichamoorthy N, Burma S. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia 2012;14:34-43.
16. Toledo LI, Murga M, Zur R, Soria R, Rodriguez A, Martinez S, et al. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol 2011; 18:721-7.
17. Peyton JD, Ahnert JR, Burris H, Britten C, Chen LC, Taberno J, et al. A dose-escalation study with the novel formulation of the oral pan-class I PI3K inhibitor BEZ235, solid dispersion system (SDS) sachet, in patients with advanced solid tumors. J Clin Oncol 29, 2011 (suppl; abstr 3066).
18. Mukherjee B, McEllin B, Camacho CV, Tomimatsu N, Sirasanagandala S, Nannepaga S, et al. EGFRvIII andDNA double-strand break repair: a molecular mechanism for radioresistance in glioblastoma. Cancer Res 2009;69:4252-9.
19. Campeau E, Ruhl VE, Rodier F, Smith CL, Rahmberg BL, Fuss JO, et al. A versatile viral system for expression and depletion of proteins in mammalian cells. PLoS One 2009;4:e6529.
20. Puliyappadamba VT, Chakraborty S, Chauncey SS, Li L, Hatanpaa KJ, Mickey B, et al. Opposing effect of EGFRWT on EGFRvIII-mediated NF-kB activation with RIP1 as a cell death switch. Cell Rep 2013;4: 764-75.
21. Yamaguchi M, Saito H, Suzuki M, Mori K. Visualization of neurogenesis in the central nervous system using nestin promoter-GFP transgenic mice. Neuroreport 2000;11:1991-6.
22. Peterson SR, Kurimasa A, Oshimura M, Dynan WS, Bradbury EM, Chen DJ. Loss of the catalytic subunit of the DNA-dependent protein kinase in DNA double-strand-break-repair mutant mammalian cells. Proc Natl Acad Sci USA 1995;92:3171-4.
23. Blaiss CA, Yu TS, Zhang G, Chen J, Dimchev G, Parada LF, et al. Temporally specified genetic ablation of neurogenesis impairs cognitive recovery after traumatic brain injury. J Neurosci 2011;31:4906-16.
24. Brachmann SM, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, et al. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVPBEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci USA 2009;106:22299-304.
25. Chanthery YH, Gustafson WC, Itsara M, Persson A, Hackett CS, Grimmer M, et al. Paracrine signaling through MYCN enhances tumor-vascular interactions in neuroblastoma. Sci Transl Med 2012; 4:115ra3.
26. Chiarini F, Grimaldi C, Ricci F, Tazzari PL, Evangelisti C, Ognibene A, et al. Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against T-cell acute lymphoblastic leukemia. Cancer Res 2010;70:8097-107.
27. Cho DC, Cohen MB, Panka DJ, Collins M, Ghebremichael M, Atkins MB, et al. The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma. Clin Cancer Res 2010;16:3628-38.
28. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008;68:9221-30.
29. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008;14:1351-6.
30. Konstantinidou G, Bey EA, Rabellino A, Schuster K, Maira MS, Gazdar AF, et al. Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations. Cancer Res 2009;69:7644-52.
31. Liu TJ, Koul D, LaFortune T, Tiao N, Shen RJ, Maira SM, et al. NVPBEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther 2009;8:2204-10.
32. Santiskulvong C, Konecny GE, Fekete M, Chen KY, Karam A, Mulholland D, et al. Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma. Clin Cancer Res 2011; 17:2373-84.
33. Schnell CR, Stauffer F, Allegrini PR, O'Reilly T, McSheehy PM, Dartois C, et al. Effects of the dual phosphatidylinositol 3-kinase/ mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res 2008;68: 6598-607.
34. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008;68:8022-30.
35. Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L, Morales FC, et al. Inhibition of PI3K/mTOR leads to adaptive resistance in matrixattached cancer cells. Cancer Cell 2012;21:227-39.
36. Fokas E, Yoshimura M, Prevo R, Higgins G, Hackl W, Maira SM, et al. NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/ mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity. Radiat Oncol 2012;7:48.
37. Cerniglia GJ, Karar J, Tyagi S, Christofidou-Solomidou M, Rengan R, Koumenis C, et al. Inhibition of autophagy as a strategy to augment radiosensitization by the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Mol Pharmacol 2012; 82:1230-40.
38. Kaina B, Christmann M, Naumann S, Roos WP.MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair (Amst) 2007;6:1079-99.
39. McEllin B, Camacho CV, Mukherjee B, Hahm B, Tomimatsu N, Bachoo RM, et al. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res 2010;70: 5457-64.
40. Roos WP, Batista LF, Naumann SC, Wick W, Weller M, Menck CF, et al. Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 2007; 26:186-97.
41. Papadopoulos MC, Saadoun S, Davies DC, Bell BA. Emerging molecular mechanisms of brain tumour oedema. Br J Neurosurg 2001;15: 101-8.
42. Bartkova J, Hamerlik P, Stockhausen MT, Ehrmann J, Hlobilkova A, LaursenH, et al. Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas. Oncogene 2010;29:5095-102.
43. Mukherjee B, Choy H, Nirodi C, Burma S. Targeting nonhomologous end-joining through epidermal growth factor receptor inhibition: rationale and strategies for radiosensitization. Semin Radiat Oncol 2010; 20:250-7.
44. Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 2009;136:823-37.
45. Sonoda Y, Ozawa T, Hirose Y, Aldape KD, McMahon M, Berger MS, et al. Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. Cancer Res 2001;61:4956-60.
46. Batey MA, Zhao Y, Kyle S, Richardson C, Slade A, Martin NM, et al. Preclinical evaluation of a novel ATM inhibitor, KU59403, in vitro and in vivo in p53 functional and dysfunctional models of human cancer. Mol Cancer Ther 2013;12:959-67.
47. Biddlestone-Thorpe L, Sajjad M, Rosenberg E, Beckta JM, Valerie NC, Tokarz M, et al. ATM kinase inhibition preferentially sensitizes p53 mutant glioma to ionizing radiation. Clin Cancer Res 2013;9:3189-200.
48. Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson CJ, Cano C, et al. Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K. Mol Cancer Ther 2012;11:1789-98.
49. Shinohara ET, Geng L, Tan J, Chen H, Shir Y, Edwards E, et al. DNAdependent protein kinase is a molecular target for the development of noncytotoxic radiation-sensitizing drugs. Cancer Res 2005;65: 4987-92.
50. Zhao Y, Thomas HD, Batey MA, Cowell IG, Richardson CJ, Griffin RJ, et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res 2006;66:5354-62.