Targeting PI3K/Akt/mTOR signaling pathway in the treatment of prostate cancer radioresistance

Critical Reviews in Oncology/Hematology

Volumn 96, Issue 3, 2015, Pages 507-517

  Chang, Lei ^a,b   Graham, Peter H ^a,b   Ni, Jie ^a,b   Hao, Jingli ^a,b   Bucci, Joseph ^a,b   Cozzi, Paul J ^a,b   Li, Yong ^a,b  

^a ST GEORGE HOSPITAL   (Australia)

^b UNIVERSITY OF NEW SOUTH WALES   (Australia)

Author keywords

Inhibitors; PI3K Akt mTOR; Prostate cancer; Radiation therapy; Radioresistance

Indexed keywords

2 (4 HYDROXYPHENYL) 4 MORPHOLINOPYRIDO[3',2':4,5]FURO[3,2 D]PYRIMIDINE; 2 MORPHOLINO 8 PHENYLCHROMONE; BUPARLISIB; DACTOLISIB; EPIDERMAL GROWTH FACTOR RECEPTOR; ERUFOSINE; EVEROLIMUS; HYPOXIA INDUCIBLE FACTOR 1; JANUS KINASE; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MULTIDRUG RESISTANCE PROTEIN 1; PALOMID 529; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; RAPAMYCIN; STAT PROTEIN; TEMSIROLIMUS; UNCLASSIFIED DRUG; WORTMANNIN; MTOR PROTEIN, HUMAN; RADIOSENSITIZING AGENT; TARGET OF RAPAMYCIN KINASE;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; CANCER GROWTH; CANCER RADIOTHERAPY; CANCER RECURRENCE; CELL DIFFERENTIATION; CELL GROWTH; CELL MOTILITY; CELL PROLIFERATION; CELL SURVIVAL; DRUG MECHANISM; DRUG RECEPTOR BINDING; ENZYME ACTIVATION; EPITHELIAL MESENCHYMAL TRANSITION; HUMAN; IN VIVO STUDY; LETHARGY; LIQUID CHROMATOGRAPHY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROSTATE CANCER; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN SECRETION; RADIATION DOSE; RADIOSENSITIVITY; RESPIRATION DEPRESSION; REVIEW; SIGNAL TRANSDUCTION; TANDEM MASS SPECTROMETRY; TUMOR MICROENVIRONMENT; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; MALE; METABOLISM; PATHOLOGY; PROSTATIC NEOPLASMS; RADIATION TOLERANCE;

HUMANS; MALE; PHOSPHATIDYLINOSITOL 3-KINASES; PROSTATIC NEOPLASMS; PROTO-ONCOGENE PROTEINS C-AKT; RADIATION TOLERANCE; RADIATION-SENSITIZING AGENTS; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84983168903     PISSN: 10408428     EISSN: 18790461     Source Type: Journal    
DOI: 10.1016/j.critrevonc.2015.07.005     Document Type: Review

References (108)

1. Abazeed M.E., Adams D.J., Hurov K.E., et al. Integrative radiogenomic profiling of squamous cell lung cancer. Cancer Res. 2013, 73:6289-6298.
2. Abraham R.T. mTOR as a positive regulator of tumor cell responses to hypoxia. Curr. Top. Microbiol. Immunol. 2004, 279:299-319.
3. Alessi D.R., Deak M., Casamayor A., et al. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr. Biol. 1997, 7:776-789.
4. Amato R.J., Wilding G., Bubley G., et al. Safety and preliminary efficacy analysis of the mTOR inhibitor ridaforolimus in patients with taxane-treated, castration-resistant prostate cancer. Clin. Genitourin Cancer 2012, 10:232-238.
5. Belka C., Jendrossek V., Pruschy M., et al. Apoptosis-modulating agents in combination with radiotherapy-current status and outlook. Int. J. Radiat. Oncol. Biol. Phys. 2004, 58:542-554.
6. Betz C., Hall M.N. Where is mTOR and what is it doing there?. J. Cell Biol. 2013, 203:563-574.
7. Betz C., Stracka D., Prescianotto-Baschong C., et al. Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology. Proc. Natl. Acad. Sci. U. S. A. 2013, 110:12526-12534.
8. Bjerke G.A., Yang C.S., Frierson H.F., et al. Activation of Akt signaling in prostate induces a TGFbeta-mediated restraint on cancer progression and metastasis. Oncogene 2013, 33:3660-3667.
9. Cao C., Subhawong T., Albert J.M., et al. Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res. 2006, 66:10040-10047.
10. Chang L., Graham P.H., Hao J., et al. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis. 2013, 4:e875.
11. Chang L., Graham P.H., Hao J., et al. Emerging roles of radioresistance in prostate cancer metastasis and radiation therapy. Cancer Metastasis Rev. 2014, 33:469-496.
12. Chang L., Graham P.H., Hao J., et al. PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways. Cell Death Dis. 2014, 5:e1437.
13. Chee K.G., Longmate J., Quinn D.I., et al. The AKT inhibitor perifosine in biochemically recurrent prostate cancer: a phase II California/Pittsburgh cancer consortium trial. Clin. Genitourin Cancer 2007, 5:433-437.
14. Chen X., Thakkar H., Tyan F., et al. Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene 2001, 20:6073-6083.
15. Coen J.J., Bae K., Zietman A.L., et al. Acute and late toxicity after dose escalation to 82 GyE using conformal proton radiation for localized prostate cancer: initial report of American College of Radiology Phase II study 03-12. Int. J. Radiat. Oncol. Biol. Phys. 2011, 81:1005-1009.
16. De Luca A., Maiello M.R., D'Alessio A., et al. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin. Ther. Targets 2012, 16(Suppl 2):S17-S27.
17. de Muga S., Hernandez S., Agell L., et al. Molecular alterations of EGFR and PTEN in prostate cancer: association with high-grade and advanced-stage carcinomas. Mod. Pathol. 2010, 23:703-712.
18. Diaz R., Nguewa P.A., Diaz-Gonzalez J.A., et al. The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer. Br. J. Cancer 2009, 100:932-940.
19. Dreher T., Zentgraf H., Abel U., et al. Reduction of PTEN and p27kip1 expression correlates with tumor grade in prostate cancer. Analysis in radical prostatectomy specimens and needle biopsies. Virchows Arch. 2004, 444:509-517.
20. Dubrovska A., Elliott J., Salamone R.J., et al. Combination therapy targeting both tumor-initiating and differentiated cell populations in prostate carcinoma. Clin. Cancer Res. 2010, 16:5692-5702.
21. Dumont R.A., Tamma M., Braun F., et al. Targeted radiotherapy of prostate cancer with a gastrin-releasing peptide receptor antagonist is effective as monotherapy and in combination with rapamycin. J. Nucl. Med. 2013, 54:762-769.
22. Eyler C.E., Rich J.N. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J. Clin. Oncol. 2008, 26:2839-2845.
23. Fang Y., Vilella-Bach M., Bachmann R., et al. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 2001, 294:1942-1945.
24. Floc'h N., Abate-Shen C. The promise of dual targeting Akt/mTOR signaling in lethal prostate cancer. Oncotarget 2012, 3:1483-1484.
25. Folkes A.J., Ahmadi K., Alderton W.K., et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-t hieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J. Med. Chem. 2008, 51:5522-5532.
26. Fresno Vara J.A., Casado E., de Castro J., et al. PI3K/Akt signalling pathway and cancer. Cancer Treat. Rev. 2004, 30:193-204.
27. Fruman D.A., Meyers R.E., Cantley L.C. Phosphoinositide kinases. Annu. Rev. Biochem. 1998, 67:481-507.
28. Gao Y., Ishiyama H., Sun M., et al. The alkylphospholipid, perifosine, radiosensitizes prostate cancer cells both in vitro and in vivo. Radiother. Oncol. 2011, 6:39.
29. Gottschalk A.R., Doan A., Nakamura J.L., et al. Inhibition of phosphatidylinositol-3-kinase causes increased sensitivity to radiation through a PKB-dependent mechanism. Int. J. Radiat. Oncol. Biol. Phys. 2005, 63:1221-1227.
30. Gravina G.L., Marampon F., Sherris D., et al. Torc1/Torc2 inhibitor, Palomid 529, enhances radiation response modulating CRM1-mediated survivin function and delaying DNA repair in prostate cancer models. Prostate 2014, 74:852-868.
31. Grewe M., Gansauge F., Schmid R.M., et al. Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Cancer Res. 1999, 59:3581-3587.
32. Guillard S., Clarke P.A., Te Poele R., et al. Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma. Cell Cycle 2009, 8:443-453.
33. Gupta A.K., Cerniglia G.J., Mick R., et al. Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002. Int. J. Radiat. Oncol. Biol. Phys. 2003, 56:846-853.
34. Hay N., Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004, 18:1926-1945.
35. Heavey S., O'Byrne K.J., Gately K. Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC. Cancer Treat. Rev. 2014, 40:445-456.
36. Hennessey D., Martin L.M., Atzberger A., et al. Exposure to hypoxia following irradiation increases radioresistance in prostate cancer cells. Urol. Oncol. 2013, 31:1106-1116.
37. Hermann P.C., Huber S.L., Herrler T., et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007, 1:313-323.
38. Hong S.W., Shin J.S., Moon J.H., et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, induces cell death through alternate routes in prostate cancer cells depending on the PTEN genotype. Apoptosis 2014, 19:895-904.
39. Horwitz E.M., Hanks G.E. External beam radiation therapy for prostate cancer. CA Cancer J. Clin. 2000, 50:349-375.
40. Howes A.L., Chiang G.G., Lang E.S., et al. The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol. Cancer Ther. 2007, 6:2505-2514.
41. Ishiyama H., Wang H., Butler E.B., et al. Schedule-dependent interactions between perifosine and radiotherapy in prostate cancer. J. Radiat. Oncol. 2013, 2:209-216.
42. Jemal A., Bray F., Center M.M., et al. Global cancer statistics. CA. Cancer J. Clin. 2011, 61:69-90.
43. Jendrossek V., Henkel M., Hennenlotter J., et al. Analysis of complex protein kinase B signalling pathways in human prostate cancer samples. BJU Int. 2008, 102:371-382.
44. Karar J., Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front. Mol. Neurosci. 2011, 4:51.
45. Karve S., Werner M.E., Sukumar R., et al. Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery. Proc. Natl. Acad. Sci. U. S. A. 2012, 109:8230-8235.
46. Kasuno K., Takabuchi S., Fukuda K., et al. Nitric oxide induces hypoxia-inducible factor 1 activation that is dependent on MAPK and phosphatidylinositol 3-kinase signaling. J. Biol. Chem. 2004, 279:2550-2558.
47. Kim D.H., Sarbassov D.D., Ali S.M., et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002, 110:163-175.
48. Kim B.Y., Kim K.A., Kwon O., et al. NF-kappaB inhibition radiosensitizes Ki-Ras-transformed cells to ionizing radiation. Carcinogenesis 2005, 26:1395-1403.
49. Kim Y., Lin Q., Glazer P.M., et al. Hypoxic tumor microenvironment and cancer cell differentiation. Curr. Mol. Med. 2009, 9:425-434.
50. Koul D., Fu J., Shen R., et al. Antitumor activity of NVP-BKM120-a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells. Clin. Cancer Res. 2012, 18:184-195.
51. Kremer C.L., Klein R.R., Mendelson J., et al. Expression of mTOR signaling pathway markers in prostate cancer progression. Prostate 2006, 66:1203-1212.
52. Kreso A., Dick J.E. Evolution of the cancer stem cell model. Cell Stem Cell 2014, 14:275-291.
53. Lam J.S., Belldegrun A.S. Salvage cryosurgery of the prostate after radiation failure. Rev. Urol. 2004, 6(Suppl 4):S27-S36.
54. Lee J.T., Steelman L.S., McCubrey J.A. Phosphatidylinositol 3'-kinase activation leads to multidrug resistance protein-1 expression and subsequent chemoresistance in advanced prostate cancer cells. Cancer Res. 2004, 64:8397-8404.
55. Lee S.H., Poulogiannis G., Pyne S., et al. A constitutively activated form of the p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice. Proc. Natl. Acad. Sci. U. S. A. 2010, 107:11002-11007.
56. Leevers S.J., Vanhaesebroeck B., Waterfield M.D. Signalling through phosphoinositide 3-kinases: the lipids take centre stage. Curr. Opin. Cell Biol. 1999, 11:219-225.
57. Lin J., Adam R.M., Santiestevan E., et al. The phosphatidylinositol 3'-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells. Cancer Res. 1999, 59:2891-2897.
58. Lin H.K., Yeh S., Kang H.Y., et al. Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc. Natl. Acad. Sci. U. S. A. 2001, 98:7200-7205.
59. Ma D.J., Galanis E., Anderson S.K., et al. A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K. Neuro Oncol. 2014, [Epub ahead of print].
60. Maira S.M., 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.
61. Maira S.M., Pecchi S., Huang A., et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol. Cancer Ther. 2012, 11:317-328.
62. Manning B.D., Cantley L.C. AKT/PKB signaling: navigating downstream. Cell 2007, 129:1261-1274.
63. Martelli A.M., Evangelisti C., Chappell W., et al. Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway. Leukemia 2011, 25:1064-1079.
64. McCall P., Gemmell L.K., Mukherjee R., et al. Phosphorylation of the androgen receptor is associated with reduced survival in hormone-refractory prostate cancer patients. Br. J. Cancer 2008, 98:1094-1101.
65. McMenamin M.E., Soung P., Perera S., et al. Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res. 1999, 59:4291-4296.
66. Morgan T.M., Koreckij T.D., Corey E. Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway. Curr. Cancer Drug Targets 2009, 9:237-249.
67. Mukherji D., Pezaro C.J., De-Bono J.S. MDV3100 for the treatment of prostate cancer. Expert Opin. Investig. Drugs 2012, 21:227-233.
68. Ni J., Cozzi P., Hao J., et al. Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway. Int. J. Biochem. Cell Biol. 2013, 45:2736-2748.
69. Ni J., Cozzi P.J., Hao J.L., et al. CD44 variant 6 is associated with prostate cancer metastasis and chemo-/radioresistance. Prostate 2014, 74:602-617.
70. Porta C., Paglino C., Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front. Oncol. 2014, 4:64.
71. Posadas E.M., Gulley J., Arlen P.M., et al. A phase II study of perifosine in androgen independent prostate cancer. Cancer Biol. Ther. 2005, 4:1133-1137.
72. Potiron V.A., Abderrhamani R., Giang E., et al. Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions. Radiother. Oncol. 2013, 106:138-146.
73. Prawettongsopon C., Asawakarn S., Suthiphongchai T. Suppression of prometastatic phenotype of highly metastatic androgen-independent rat prostate cancer MLL cell line by PI3K inhibitor LY294002. Oncol. Res. 2009, 17:301-309.
74. Prevo R., Deutsch E., Sampson O., et al. Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res. 2008, 68:5915-5923.
75. Reid A.H., Attard G., Ambroisine L., et al. Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br. J. Cancer 2010, 102:678-684.
76. Rodon J., Brana I., Siu L.L., et al. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest. New Drugs 2014, 32:670-681.
77. Rosenzweig K.E., Youmell M.B., Palayoor S.T., et al. Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. Clin. Cancer Res. 1997, 3:1149-1156.
78. Rudner J., Ruiner C.E., Handrick R., et al. The Akt-inhibitor Erufosine induces apoptotic cell death in prostate cancer cells and increases the short term effects of ionizing radiation. Radiother. Oncol. 2010, 5:108.
79. Rycaj K., Tang D.G. Cancer stem cells and radioresistance. Int. J. Radiat. Biol. 2014.
80. Sabatini D.M. mTOR and cancer: insights into a complex relationship. Nat. Rev. Cancer 2006, 6:729-734.
81. Sahlberg S.H., Spiegelberg D., Glimelius B., et al. Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells. PLoS One 2014, 9:e94621.
82. Sansal I., Sellers W.R. The biology and clinical relevance of the PTEN tumor suppressor pathway. J. Clin. Oncol. 2004, 22:2954-2963.
83. Sarkaria J.N., Galanis E., Wu W., et al. Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks. Clin. Cancer Res. 2010, 16:5573-5580.
84. Schiewer M.J., Den R., Hoang D.T., et al. mTOR is a selective effector of the radiation therapy response in androgen receptor-positive prostate cancer. Endocr. Relat. Cancer 2012, 19:1-12.
85. Schmitz M., Grignard G., Margue C., et al. Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int. J. Cancer 2007, 120:1284-1292.
86. Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem. Pharmacol. 2002, 64:993-998.
87. Seol J.W., Lee Y.J., Kang H.S., et al. Wortmannin elevates tumor necrosis factor-related apoptosis-inducing ligand sensitivity in LNCaP cells through down-regulation of IAP-2 protein. Exp. Oncol. 2005, 27:120-124.
88. 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.
89. Siegel R., Naishadham D., Jemal A. Cancer statistics, 2012. CA Cancer J. Clin. 2012, 62:10-29.
90. Sircar K., Yoshimoto M., Monzon F.A., et al. PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer. J. Pathol. 2009, 218:505-513.
91. Skvortsova I., Skvortsov S., Stasyk T., et al. Intracellular signaling pathways regulating radioresistance of human prostate carcinoma cells. Proteomics 2008, 8:4521-4533.
92. Sparks C.A., Guertin D.A. Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene 2010, 29:3733-3744.
93. Stephens L., Anderson K., Stokoe D., et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 1998, 279:710-714.
94. Sun S.Y. mTOR kinase inhibitors as potential cancer therapeutic drugs. Cancer Lett. 2013, 340:1-8.
95. Taylor B.S., Schultz N., Hieronymus H., et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010, 18:11-22.
96. Teng D.H., Hu R., Lin H., et al. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res. 1997, 57:5221-5225.
97. Vanhaesebroeck B., Leevers S.J., Ahmadi K., et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 2001, 70:535-602.
98. Vink S.R., Lagerwerf S., Mesman E., et al. Radiosensitization of squamous cell carcinoma by the alkylphospholipid perifosine in cell culture and xenografts. Clin. Cancer Res. 2006, 12:1615-1622.
99. Vink S.R., Schellens J.H., Beijnen J.H., et al. Phase I and pharmacokinetic study of combined treatment with perifosine and radiation in patients with advanced solid tumours. Radiother. Oncol. 2006, 80:207-213.
100. Vora S.A., Wong W.W., Schild S.E., et al. Outcome and toxicity for patients treated with intensity modulated radiation therapy for localized prostate cancer. J. Urol. 2013, 190:521-526.
101. Wallin J.J., Edgar K.A., Guan J., et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol. Cancer Ther. 2011, 10:2426-2436.
102. Wullschleger S., Loewith R., Hall M.N. TOR signaling in growth and metabolism. Cell 2006, 124:471-484.
103. Xue Q., Hopkins B., Perruzzi C., et al. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Res. 2008, 68:9551-9557.
104. Zaza G., Granata S., Tomei P., et al. mTOR inhibitors and renal allograft: Yin and Yang. J. Nephrol. 2014.
105. Zhong H., Chiles K., Feldser D., et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 2000, 60:1541-1545.
106. Zhou X., Lu X., Richard C., et al. 1-O-octadecyl-2-O-methyl-glycerophosphocholine inhibits the transduction of growth signals via the MAPK cascade in cultured MCF-7 cells. J. Clin. Invest. 1996, 98:937-944.
107. Zhou B.B., Zhang H., Damelin M., et al. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat. Rev. Drug Discov. 2009, 8:806-823.
108. Zhu W., Fu W., Hu L. NVP-BEZ235, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, prominently enhances radiosensitivity of prostate cancer cell line PC-3. Cancer Biother. Radiopharm. 2013, 28:665-673.