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 Research

Volumn 69, Issue 19, 2009, Pages 7644-7652

  Konstantinidou, Georgia ^a,c   Bey, Erik A ^b   Rabellino, Andrea ^a   Schuster, Katja ^a   Maira, Michael S ^d   Gazdar, Adi F ^a   Amici, Augusto ^c   Boothman, David A ^b   Scaglioni, Pier Paolo ^a  

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

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

^c UNIVERSITY OF CAMERINO   (Italy)

^d NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; BEZ 235; K RAS PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; RADIOSENSITIZING AGENT; RAPAMYCIN; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; APOPTOSIS; ARTICLE; CANCER CELL CULTURE; CANCER CELL DESTRUCTION; CANCER RADIOTHERAPY; CELL CYCLE ARREST; ENZYME ACTIVATION; FEMALE; GENE EXPRESSION; GENE MUTATION; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; IONIZING RADIATION; LUNG NON SMALL CELL CANCER; MOUSE; NONHUMAN; ONCOGENE K RAS; PRIORITY JOURNAL; RADIATION RESPONSE; RADIOSENSITIZATION;

ANIMALS; APOPTOSIS; CARCINOMA, NON-SMALL-CELL LUNG; CELL LINE, TUMOR; COMBINED MODALITY THERAPY; FEMALE; GENES, RAS; HUMANS; IMIDAZOLES; LUNG NEOPLASMS; MICE; MICE, NUDE; MUTATION; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASES; QUINOLINES; RADIATION-SENSITIZING AGENTS; TOR SERINE-THREONINE KINASES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 70350228529     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-09-0823     Document Type: Article

References (43)

1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71-96.
2. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606-619 (Pubitemid 44100518)
3. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006;441:424-430 (Pubitemid 44050136)
4. Ding L, Getz G, Wheeler DA, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008;455:1069-1075
5. Brognard J, Clark AS, Ni Y, Dennis PA. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 2001;61:3986-3997 (Pubitemid 32720961)
6. Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci US A 2005;102: 802-807 (Pubitemid 40282746)
7. Bader AG, Kang S, Vogt PK. Cancer-specific mutations in PIK3CA are oncogenic in vivo . Proc Natl Acad Sci US A 2006;103:1475-1479 (Pubitemid 43191190)
8. Engelman JA, Chen L, Tan X, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008;14:1351-1356
9. Gupta S, Ramjaun AR, Haiko P, et al. Binding of ras to phosphoinositide 3-kinase p110α is required for ras-driven tumorigenesis in mice. Cell 2007;129: 957-968 (Pubitemid 46802703)
10. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007;129:1261-1274
11. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science (New York, NY) 2005;307: 1098-1101
12. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci US A 2004; 101:13306-13311 (Pubitemid 39209661)
13. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139 (Pubitemid 38637993)
14. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, NY) 2004;304: 1497-1500 (Pubitemid 38720929)
15. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786-792 (Pubitemid 40271173)
16. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73. (Pubitemid 40629469)
17. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev 2003;3:11-22. (Pubitemid 37328883)
18. Wislez M, Spencer ML, Izzo JG, et al. Inhibition of mammalian target of rapamycin reverses alveolar epithelial neoplasia induced by oncogenic K-ras. Cancer Res 2005;65:3226-3235 (Pubitemid 40524605)
19. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev 2006;6:729-734
20. Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008;118:3065-3074
21. Maira SM, Stauffer F, Brueggen J, 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;7:1851-1863
22. Schnell CR, Stauffer F, Allegrini PR, 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;68:6598-6607
23. Serra V, Markman B, Scaltriti 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;68:8022-8030
24. Eichhorn PJ, Gili M, Scaltriti M, 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;68:9221-9230
25. Bozulic L, Surucu B, Hynx D, Hemmings BA. PKBa/ Akt1 acts downstream of DNA-PK in the DNA doublestrand break response and promotes survival. Mol Cell 2008;30:203-213 (Pubitemid 351626686)
26. Phelps RM, Johnson BE, Ihde DC, et al. NCI-Navy Medical Oncology Branch cell line data base. J Cell Biochem Suppl 1996;24:32-91. (Pubitemid 26277220)
27. Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc 2006;1:2315-2319
28. Boothman DA, Greer S, Pardee AB. Potentiation of halogenated pyrimidine radiosensitizers in human carcinoma cells by β-lapachone (3,4-dihydro-2,2-dimethyl- 2H-naphtho[1,2-b]pyran-5,6-dione), a novel DNA repair inhibitor. Cancer Res 1987;47:5361-5366
29. Scaglioni PP, Yung TM, Cai LF, et al. A CK2- dependent mechanism for degradation of the PML tumor suppressor. Cell 2006;126:269-283
30. Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 1991;139:271-279
31. Fisher GH, Wellen SL, Klimstra D, et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 2001;15: 3249-3262 (Pubitemid 34008191)
32. Valenzuela MT, Guerrero R, Nunez MI, et al. PARP-1 modifies the effectiveness of p53-mediated DNA damage response. Oncogene 2002;21:1108-1116 (Pubitemid 34174523)
33. Kim IA, Bae SS, Fernandes A, et al. Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines. Cancer Res 2005;65:7902-7910 (Pubitemid 41297268)
34. Gupta AK, Bakanauskas VJ, Cerniglia GJ, et al. The Ras radiation resistance pathway. Cancer Res 2001;61: 4278-4282
35. Yamamoto H, Shigematsu H, Nomura M, et al. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 2008;68:6913-6921
36. Fairchild A, Harris K, Barnes E, et al. Palliative thoracic radiotherapy for lung cancer: a systematic review. J Clin Oncol 2008;26:4001-4011
37. Iwasa T, Okamoto I, Suzuki M, et al. Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines. Clin Cancer Res 2008;14:6496-6504
38. Inoue A, Nukiwa T. Gene mutations in lung cancer: promising predictive factors for the success of molecular therapy. PLoS Med 2005;2:e13. (Pubitemid 40412725)
39. Huncharek M, Muscat J, Geschwind JF. K-ras oncogene mutation as a prognostic marker in nonsmall cell lung cancer: a combined analysis of 881 cases. Carcinogenesis 1999;20:1507-1510 (Pubitemid 29385437)
40. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005;2:e17. (Pubitemid 40412734)
41. Vazquez A, Bond EE, Levine AJ, Bond GL. The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov 2008;7:979-987
42. Albert JM, Kim KW, Cao C, Lu B. Targeting the Akt/ mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther 2006;5: 1183-1189 (Pubitemid 43881310)
43. Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe: a molecular definition. Oncogene 2004;23:2825-2837 (Pubitemid 38638845)