MTOR inhibitors in advanced renal cell carcinoma

Hematology/Oncology Clinics of North America

Volumn 25, Issue 4, 2011, Pages 835-852

  Voss, Martin H ^a   Molina, Ana M ^a   Motzer, Robert J ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

Kidney neoplasms; MTOR; Renal cell carcinoma; Targeted therapy; Treatment resistance

Indexed keywords

BEVACIZUMAB; CYCLIN D1; EPIDERMAL GROWTH FACTOR; EVEROLIMUS; FIBROBLAST GROWTH FACTOR; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 2ALPHA; INITIATION FACTOR 4E; INITIATION FACTOR 4E BINDING PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE; MYC PROTEIN; OCTAMER TRANSCRIPTION FACTOR 4; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE; PROTEIN KINASE B; RAPAMYCIN; SERUM AND GLUCOCORTICOID REGULATED KINASE 1; SOMATOMEDIN C; SORAFENIB; STAT3 PROTEIN; SUNITINIB; TEMSIROLIMUS; TIVOZANIB; TRANSFORMING GROWTH FACTOR ALPHA; VON HIPPEL LINDAU PROTEIN;

ABDOMINAL PAIN; ADVANCED CANCER; ANEMIA; ANOREXIA; ANTINEOPLASTIC ACTIVITY; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; ASTHENIA; BINDING AFFINITY; CALCIUM CELL LEVEL; CONSTIPATION; COUGHING; CREATININE BLOOD LEVEL; DIARRHEA; DRUG ERUPTION; DRUG FEVER; DRUG INDUCED HEADACHE; DRUG MECHANISM; DYSGEUSIA; DYSPNEA; EPISTAXIS; FATIGUE; HUMAN; HYPERCHOLESTEROLEMIA; HYPERGLYCEMIA; HYPERLIPIDEMIA; HYPOPHOSPHATEMIA; IMMUNOHISTOCHEMISTRY; IMMUNOREACTIVITY; INFECTION; KIDNEY CARCINOMA; LYMPHOCYTOPENIA; NAUSEA; NEUTROPENIA; PAIN; PERIPHERAL EDEMA; PHASE 3 CLINICAL TRIAL (TOPIC); PNEUMONIA; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN SYNTHESIS; PRURITUS; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; STOMATITIS; THROMBOCYTOPENIA; VOMITING;

CARCINOMA, RENAL CELL; CLINICAL TRIALS AS TOPIC; HUMANS; KIDNEY NEOPLASMS; PROTEIN KINASE INHIBITORS; SIROLIMUS; TOR SERINE-THREONINE KINASES; TREATMENT OUTCOME;

EID: 79960374012     PISSN: 08898588     EISSN: 15581977     Source Type: Journal    
DOI: 10.1016/j.hoc.2011.04.008     Document Type: Review

References (105)

1. Escudier B., Eisen T., Stadler W.M., et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356(2):125-134.
2. Motzer R.J., Hutson T.E., Tomczak P., et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007, 356(2):115-124.
3. Sternberg C.N., Davis I.D., Mardiak J., et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010, 28(6):1061-1068.
4. Hudes G., Carducci M., Tomczak P., et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007, 356(22):2271-2281.
5. Escudier B., Pluzanska A., Koralewski P., et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007, 370(9605):2103-2111.
6. Motzer R.J., Escudier B., Oudard S., et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008, 372(9637):449-456.
7. Katso R., Okkenhaug K., Ahmadi K., et al. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001, 17:615-675.
8. Gibbons J.J., Abraham R.T., Yu K. Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. Semin Oncol 2009, 36(Suppl 3):S3-S17.
9. Sansal I., Sellers W.R. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004, 22(14):2954-2963.
10. Manning B.D., Cantley L.C. AKT/PKB signaling: navigating downstream. Cell 2007, 129(7):1261-1274.
11. Wullschleger S., Loewith R., Hall M.N. TOR signaling in growth and metabolism. Cell 2006, 124(3):471-484.
12. Peng T., Golub T.R., Sabatini D.M. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol Cell Biol 2002, 22(15):5575-5584.
13. Kim J.E., Chen J. Regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 2004, 53(11):2748-2756.
14. Hay N., Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004, 18(16):1926-1945.
15. Hudes G.R. Targeting mTOR in renal cell carcinoma. Cancer 2009, 115(Suppl 10):2313-2320.
16. Azim H., Azim H.A., Escudier B. Targeting mTOR in cancer: renal cell is just a beginning. Target Oncol 2010, 5:269-280.
17. Guertin D.A., Sabatini D.M. Defining the role of mTOR in cancer. Cancer Cell 2007, 12(1):9-22.
18. Thomas G.V., Tran C., Mellinghoff I.K., et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 2006, 12(1):122-127.
19. Sarbassov D.D., Guertin D.A., Ali S.M., et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005, 307(5712):1098-1101.
20. Birkenkamp K.U., Coffer P.J. Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors. Biochem Soc Trans 2003, 31(Pt 1):292-297.
21. Sarbassov D.D., Ali S.M., Kim D.H., et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004, 14(14):1296-1302.
22. Toschi A., Lee E., Gadir N., et al. Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. J Biol Chem 2008, 283(50):34495-34499.
23. Gordan J.D., Simon M.C. Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev 2007, 17(1):71-77.
24. Kondo K., Kim W.Y., Lechpammer M., et al. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 2003, 1(3):E83.
25. Bhatt R.S., Landis D.M., Zimmer M., et al. Hypoxia-inducible factor-2alpha: effect on radiation sensitivity and differential regulation by an mTOR inhibitor. BJU Int 2008, 102(3):358-363.
26. Lin F., Zhang P.L., Yang X.J., et al. Morphoproteomic and molecular concomitants of an overexpressed and activated mTOR pathway in renal cell carcinomas. Ann Clin Lab Sci 2006, 36(3):283-293.
27. Robb V.A., Karbowniczek M., Klein-Szanto A.J., et al. Activation of the mTOR signaling pathway in renal clear cell carcinoma. J Urol 2007, 177(1):346-352.
28. Abou Youssif T., Fahmy M.A., Koumakpayi I.H., et al. The mammalian target of rapamycin pathway is widely activated without PTEN deletion in renal cell carcinoma metastases. Cancer 2011, 117(2):290-300.
29. Pantuck A.J., Seligson D.B., Klatte T., et al. Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer 2007, 109(11):2257-2267.
30. Sehgal S.N., Baker H., Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo) 1975, 28(10):727-732.
31. Vezina C., Kudelski A., Sehgal S.N. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 1975, 28(10):721-726.
32. Sehgal S.N., Molnar-Kimber K., Ocain T.D., et al. Rapamycin: a novel immunosuppressive macrolide. Med Res Rev 1994, 14(1):1-22.
33. Bjornsti M.A., Houghton P.J. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004, 4(5):335-348.
34. Eng C.P., Sehgal S.N., Vezina C. Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 1984, 37(10):1231-1237.
35. Luan F.L., Ding R., Sharma V.K., et al. Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 2003, 63(3):917-926.
36. Meric-Bernstam F., Gonzalez-Angulo A.M. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009, 27(13):2278-2287.
37. Panwalkar A., Verstovsek S., Giles F.J. Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer 2004, 100(4):657-666.
38. Abraham R.T., Gibbons J.J. The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res 2007, 13(11):3109-3114.
39. Dudkin L., Dilling M.B., Cheshire P.J., et al. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 2001, 7(6):1758-1764.
40. Geoerger B., Kerr K., Tang C.B., et al. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 2001, 61(4):1527-1532.
41. Shi Y., Gera J., Hu L., et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002, 62(17):5027-5034.
42. Yu K., Toral-Barza L., Discafani C., et al. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 2001, 8(3):249-258.
43. Buckner J.C., Forouzesh B., Erlichman C., et al. Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer. Invest New Drugs 2010, 28(3):334-342.
44. Raymond E., Alexandre J., Faivre S., et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 2004, 22(12):2336-2347.
45. Hidalgo M., Buckner J.C., Erlichman C., et al. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 2006, 12(19):5755-5763.
46. Atkins M.B., Hidalgo M., Stadler W.M., et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004, 22(5):909-918.
47. Motzer R.J., Bacik J., Murphy B.A., et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002, 20:289-296.
48. Dutcher J.P., de Souza P., McDermott D., et al. Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med Oncol 2009, 26(2):202-209.
49. Motzer R.J., Bacik J., Mariani T., et al. Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol 2002, 20(9):2376-2381.
50. Mackenzie M.J., Rini B.I., Elson P., et al. Temsirolimus in VEGF-refractory metastatic renal cell carcinoma. Ann Oncol 2011, 22(1):145-148.
51. Motzer R.J., Bacik J., Schwartz L.H., et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004, 22(3):454-463.
52. Eisen H.J., Tuzcu E.M., Dorent R., et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003, 349(9):847-858.
53. Neuhaus P., Klupp J., Langrehr J.M. mTOR inhibitors: an overview. Liver Transpl 2001, 7(6):473-484.
54. Pascual J. Everolimus in clinical practice-renal transplantation. Nephrol Dial Transplant 2006, 21(Suppl 3):iii18-iii23.
55. Boulay A., Zumstein-Mecker S., Stephan C., et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 2004, 64(1):252-261.
56. O'Donnell A., Faivre S., Burris H.A., et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008, 26(10):1588-1595.
57. Tanaka C., O'Reilly T., Kovarik J.M., et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008, 26(10):1596-1602.
58. Amato R.J., Jac J., Giessinger S., et al. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 2009, 115(11):2438-2446.
59. Cella D., Yount S., Brucker P.S., et al. Development and validation of a scale to measure disease-related symptoms of kidney cancer. Value Health 2007, 10(4):285-293.
60. Aaronson N.K., Ahmedzai S., Bergman B., et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993, 85(5):365-376.
61. Motzer R.J., Escudier B., Oudard S., et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010, 116:4256-4265.
62. Knox J.J., Kay A.C., Schiff E., et al. First-line everolimus followed by second-line sunitinib versus the opposite treatment sequence in patients with metastatic renal cell carcinoma (mRCC). Proc Am Soc Clinical Oncol 2010, 28(Suppl 15). [abstract: TPS232].
63. Patel P.H., Senico P.L., Curiel R.E., et al. Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 2009, 7(1):24-27.
64. Molina A.M., Feldman D.R., Ginsberg M.S., et al. Phase I trial sunitinib plus everolimus in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 2011, 29(Suppl). [abstract: 311].
65. Patnaik A., Ricart A., Cooper J.S., et al. A phase I, pharmacokinetic and pharmacodynamic study of sorafenib (S), a multi-targeted kinase inhibitor in combination with temsirolimus (T), an mTOR inhibitor in patients with advanced solid malignancies. J Clin Oncol 2007, 25(Suppl 18). Annual Meeting Proceedings Part I, [abstract: 3512].
66. Rosenberg J.E., Weinberg V.K., Claros C., et al. Phase I study of sorafenib and RAD001 for metastatic clear cell renal cell carcinoma. J Clin Oncol 2008, 26(Suppl). [abstract: 5109].
67. Kabbinavar F.F., Srinivas S., Hauke R.J., et al. A phase I trial of combined tivozanib (AV-951) and temsirolimus therapy in patients (pts) with renal cell carcinoma (RCC). J Clin Oncol 2011, 29(Suppl 7). [abstract: 330].
68. Merchan J.R., Liu G., Fitch T., et al. Phase I/II trial of CCI-779 and bevacizumab in stage IV renal cell carcinoma: phase I safety and activity results. J Clin Oncol 2007, 25(Suppl 18). Annual Meeting Proceedings Part I, [abstract: 5034].
69. Escudier B., Negrier S., Gravis G., et al. Can the combination of temsirolimus and bevacizumab improve the treatment of metastatic renal cell carcinoma (mRCC)? Result of the randomized TORAVA phase II trial. J Clin Oncol 2010, 28(Suppl 15). [abstract: 4516].
70. Zafar Y., Bendell J., Lager J., et al. Preliminary results of a phase I study of bevacizumab (BV) in combination with everolimus (E) in patients with advanced solid tumors. J Clin Oncol 2006, 24(Suppl 18). [abstract: 3097].
71. Hainsworth J.D., Spigel D.R., Burris H.A., et al. Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J Clin Oncol 2010, 28(13):2131-2136.
72. Yang J.C., Haworth L., Sherry R.M., et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003, 349(5):427-434.
73. Rini B.I., Halabi S., Rosenberg J.E., et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008, 26:5422-5428.
74. Ravaud A., Bajetta E., Kay A.C., et al. Everolimus with bevacizumab versus interferon alfa-2a plus bevacizumab as first-line therapy in patients with metastatic clear cell renal cell carcinoma. J Clin Oncol 2010, 28(Suppl 15). [abstract: TPS238].
75. Rodriguez-Pascual J., Cheng E., Maroto P., et al. Emergent toxicities associated with the use of mTOR inhibitors in patients with advanced renal carcinoma. Anticancer Drugs 2010, 21(5):478-486.
76. Li J., DeFea K., Roth R.A. Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway. J Biol Chem 1999, 274(14):9351-9356.
77. Ozes O.N., Akca H., Mayo L.D., et al. A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci U S A 2001, 98(8):4640-4645.
78. Manning B.D. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 2004, 167(3):399-403.
79. Bellmunt J., Szczylik C., Feingold J., et al. Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann Oncol 2008, 19(8):1387-1392.
80. American Diabetes Association Standards of medical care in diabetes-2010. Diabetes Care 2010, 33(Suppl 1):S11-S61.
81. Nathan D.M., Buse J.B., Davidson M.B., et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009, 32(1):193-203.
82. Grundy S.M., Cleeman J.I., Merz C.N., et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004, 110(2):227-239.
83. Pablo M., Hudes G., Dutcher J., et al. Radiographic findings of drug-induced pneumonitis and clinical correlation in patients with advanced renal cell carcinoma treated with temsirolimus. Eur J Cancer 2009, 7(Suppl 2):426-427.
84. White D.A., Camus P., Endo M., et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 2010, 182(3):396-403.
85. Duerr M., Glander P., Diekmann F., et al. Increased incidence of angioedema with ACE inhibitors in combination with mTOR inhibitors in kidney transplant recipients. Clin J Am Soc Nephrol 2010, 5(4):703-708.
86. Parithivel K., Ramaiya N., Jagannathan J.P., et al. Everolimus- and temsirolimus-associated enteritis: report of three cases. J Clin Oncol 2011, 29(14):e404-e406.
87. Wan X., Harkavy B., Shen N., et al. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 2007, 26(13):1932-1940.
88. Shi Y., Yan H., Frost P., et al. Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 2005, 4(10):1533-1540.
89. Tamburini J., Chapuis N., Bardet V., et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood 2008, 111(1):379-382.
90. O'Reilly K.E., Rojo F., She Q.B., et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006, 66(3):1500-1508.
91. Sun S.Y., Rosenberg L.M., Wang X., et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 2005, 65(16):7052-7058.
92. Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005, 8(3):179-183.
93. Huang J., Manning B.D. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009, 37(Pt 1):217-222.
94. Breuleux M., Klopfenstein M., Stephan C., et al. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther 2009, 8(4):742-753.
95. Gupta M., Ansell S.M., Novak A.J., et al. Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood 2009, 114(14):2926-2935.
96. 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(9):3065-3074.
97. Albert S., Serova M., Dreyer C., et al. New inhibitors of the mammalian target of rapamycin signaling pathway for cancer. Expert Opin Investig Drugs 2010, 19(8):919-930.
98. Courtney K.D., Corcoran R.B., Engelman J.A. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010, 28(6):1075-1083.
99. Figlin R.A., de Souza P., McDermott D., et al. Analysis of PTEN and HIF-1alpha and correlation with efficacy in patients with advanced renal cell carcinoma treated with temsirolimus versus interferon-alpha. Cancer 2009, 115(16):3651-3660.
100. Cho D., Signoretti S., Dabora S., et al. Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 2007, 5(6):379-385.
101. Di Nicolantonio F., Arena S., Tabernero J., et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 2010, 120(8):2858-2866.
102. MacConaill L.E., Campbell C.D., Kehoe S.M., et al. Profiling critical cancer gene mutations in clinical tumor samples. PLoS One 2009, 4(11):e7887.
103. Thomas R.K., Baker A.C., Debiasi R.M., et al. High-throughput oncogene mutation profiling in human cancer. Nat Genet 2007, 39(3):347-351.
104. Gattenlohner S., Etschmann B., Riedmiller H., et al. Lack of KRAS and BRAF mutation in renal cell carcinoma. Eur Urol 2009, 55(6):1490-1491.
105. Rochlitz C.F., Peter S., Willroth G., et al. Mutations in the ras protooncogenes are rare events in renal cell cancer. Eur J Cancer 1992, 28(2-3):333-336.