Sunitinib resistance in renal cell carcinoma
Main Article Content
Keywords
renal cell carcinoma, sunitinib, resistance, kidney cancer
Abstract
Of the many targeted therapies introduced since 2006, sunitinib has carved its way to become the most commonly used first-line therapy for the treatment of metastatic renal cell carcinoma (RCC). Despite significant improvements in progression-free survival, 30% of the patients are intrinsically resistant to sunitinib and the remaining 70% who respond initially will eventually become resistant in 6–15 months. While the molecular mechanisms of acquired resistance to sunitinib have been unravelling at a rapid rate, the mechanisms of intrinsic resistance remain elusive. Combination therapy, sunitinib rechallenge and sequential therapy have been investigated as means to overcome resistance to sunitinib. Of these, sequential therapy appears to be the most promising strategy. This mini review summarises our emerging understanding of the molecular mechanisms, and the strategies employed to overcome sunitinib resistance.
References
1. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009; 27:3584-3590.
2. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456.
3. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124.
4. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061-1068.
5. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427-434.
6. Hudes GR. mTOR as a target for therapy of renal cancer. Clin Adv Hematol Oncol. 2007;5:772-774.
7. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281.
8. Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004;22:4991-5004.
9. Arai E, Kanai Y. Genetic and epigenetic alterations during renal carcinogenesis. Int J Clin Exp Pathol. 2010;4:58-73.
10. Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM, Baylin SB. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A. 1994;91:9700-9704.
11. Clark PE. The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy. Kidney Int. 2009:76:939-945.
12. Pal SK, Quinn DI. Differentiating mTOR inhibitors in renal cell carcinoma. Cancer Treat Rev. 2013;39:709-719.
13. Linehan WM, Vasselli J, Srinivasan R, Walther MM, Merino M, Choyke P, Vocke C, Schmidt L, Isaacs JS, Glenn G, Toro J, Zbar B, Bottaro D, Neckers L. Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res. 2004;10(18 Pt 2):6282S-6289S.
14. Morais C, Johnson DW, Gobe GC. The VHL-HIF signaling in renal cell carcinoma: Promises and pitfalls. In: Amato RJ (Ed). Emerging Research and Treatments in Renal Cell Carcinoma. InTech Publishers, Coratia 2011; p. 57-82.
15. Huang LE, Bunn HF. Hypoxia-inducible factor and its biomedical relevance. J Biol Chem. 2003;278:19575-19578.
16. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271-275.
17. Maynard MA, Ohh M. Von Hippel-Lindau tumor suppressor protein and hypoxia-inducible factor in kidney cancer. Am J Nephrol. 2004;24:1-13.
18. Baldewijns MM, van Vlodrop IJ, Vermeulen PB, Soetekouw PM, van Engeland M, de Bruine AP. VHL and HIF signalling in renal cell carcinogenesis. J Pathol. 2010;221:125-138.
19. Maynard MA, Qi H, Chung J, Lee EH, Kondo Y, Hara S, et al. Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem. 2003;278:11032-11040.
20. Stebbins CE, Kaelin WG, Jr., Pavletich NP. Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science. 1999;284:455-461.
21. Kaelin WG. The von Hippel-Lindau tumor suppressor protein: roles in cancer and oxygen sensing. Cold Spring Harb Symp Quant Biol. 2005;70:159-166.
22. Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. Embo J. 2000;19:4298-4309.
23. Salceda S, Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem. 1997;272:22642-22647.
24. Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology (Williston Park). 2005;69 Suppl 3:4-10.
25. Cebe-Suarez S, Zehnder-Fjallman A, Ballmer-Hofer K. The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci. 2006;63:601-615.
26. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011-1027.
27. Roy H, Bhardwaj S, Yla-Herttuala S. Biology of vascular endothelial growth factors. FEBS Lett. 2006;580:2879-2887.
28. Stuttfeld E, Ballmer-Hofer K. Structure and function of VEGF receptors. IUBMB Life. 2009;61:915-922.
29. Tammela T, Enholm B, Alitalo K, Paavonen K. The biology of vascular endothelial growth factors. Cardiovasc Res. 2005;65:550-563.
30. Thurston G, Kitajewski J. VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis. Br J Cancer. 2008;99:1204-1209.
31. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol. 2006;7:359-371.
32. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6:389-395.
33. Hellstrom M, Kalen M, Lindahl P, Abramsson A, Betsholtz C. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development. 1999;126:3047-3055.
34. Labrecque L, Lamy S, Chapus A, Mihoubi S, Durocher Y, Cass B, Bojanowski MW, Gingras D, Béliveau R. Combined inhibition of PDGF and VEGF receptors by ellagic acid, a dietary-derived phenolic compound. Carcinogenesis. 2005;26:821-826.
35. Ostman A. PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev. 2004;15:275-286.
36. Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27:2278-2287.
37. Populo H, Lopes JM, Soares P. The mTOR Signalling Pathway in Human Cancer. Int J Mol Sci. 2012;13:1886-1918.
38. Kucejova B, Pena-Llopis S, Yamasaki T, Sivanand S, Tran TA, Alexander S, Alexander S, Wolff NC, Lotan Y, Xie XJ, Kabbani W, Kapur P, Brugarolas J. Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma. Mol Cancer Res. 2011;9:1255-1265.
39. Weichhart T. Mammalian target of rapamycin: a signaling kinase for every aspect of cellular life. Methods Mol Biol. 2012;821:1-14.
40. Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:125-127.
41. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355:1345-1356.
42. Linehan WM, Bratslavsky G, Pinto PA, Schmidt LS, Neckers L, Bottaro DP, Srinivasan R. Molecular diagnosis and therapy of kidney cancer. Annu Rev Med. 2010;61:329-343.
43. Gomez-Pinillos A, Ferrari AC. mTOR signaling pathway and mTOR inhibitors in cancer therapy. Hematol Oncol Clin North Am. 2012;26:483-505.
44. Figlin RA, Kaufmann I, Brechbiel J. Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: new strategies for overcoming resistance to VEGFR and mTORC1 inhibitors. Int J Cancer. 2013;133:788-796.
45. Zhou H, Huang S. Role of mTOR signaling in tumor cell motility, invasion and metastasis. Curr Protein Pept Sci. 2011;12:30-42.
46. Banumathy G, Cairns P. Signaling pathways in renal cell carcinoma. Cancer Biol Ther. 2010;10:658-664.
47. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8:579-591.
48. Ainsworth NL, Lee JS, Eisen T. Impact of anti-angiogenic treatments on metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2009;9:1793-1805.
49. Zhou H, Luo Y, Huang S. Updates of mTOR inhibitors. Anticancer Agents Med Chem. 2010;10:571-581.
50. Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res. 2006;66:5549-5554.
51. Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, Booth BP, Verbois SL, Morse DE, Liang CY, Chidambaram N, Jiang JX, Tang S, Mahjoob K, Justice R, Pazdur R. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13:1367-1373.
52. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:16-24.
53. Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD. Sunitinib in patients with metastatic renal cell carcinoma. Jama. 2006;295:2516-2524.
54. Britten CD, Kabbinavar F, Hecht JR, Bello CL, Li J, Baum C, Slamon D. A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period. Cancer Chemother Pharmacol. 2008;61:515-524.
55. Dutcher JP. Recent developments in the treatment of renal cell carcinoma. Ther Adv Urol. 2013;5:338-353.
56. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10:992-1000.
57. Porta C, Sabbatini R, Procopio G, Paglino C, Galligioni E, Ortega C. Primary resistance to tyrosine kinase inhibitors in patients with advanced renal cell carcinoma: state-of-the-science. Expert Rev Anticancer Ther. 2012;12:1571-1577.
58. Heng DY, Mackenzie MJ, Vaishampayan UN, Bjarnason GA, Knox JJ, Tan MH, Wood L, Wang Y, Kollmannsberger C, North S, Donskov F, Rini BI, Choueiri TK.. Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy. Ann Oncol. 2012;23:1549-1555.
59. Busch J, Seidel C, Weikert S, Wolff I, Kempkensteffen C, Weinkauf L, Hinz S, Magheli A, Miller K, Grünwald V. Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma. BMC Cancer. 2011;11:295.
60. Santos N, Wenger JB, Havre P, Liu Y, Dagan R, Imanirad I, Ivey AM, Zlotecki RA, Algood CB, Gilbert SM, Allegra CJ, Okunieff P, Vieweg J, Dang NH, Luesch H, Dang LH. Combination therapy for renal cell cancer: what are possible options? Oncology. 2011;81:220-229.
61. Ravaud A, Gross-Goupil M. Overcoming resistance to tyrosine kinase inhibitors in renal cell carcinoma. Cancer Treat Rev. 2012;38:996-1003.
62. Rini BI, Flaherty K. Clinical effect and future considerations for molecularly-targeted therapy in renal cell carcinoma. Urol Oncol. 2008;26:543-549
63. Simon T, Gobe G, Wu C, Ko F, C. M. Molecular mechanisms of sunitinib resistance in renal cell carcinoma. In: Morais C (Ed). Advances in drug resistance research. Nova Science Publishers, Inc. NY, USA; 2014. p. 225-245.
64. Su SC, Hu X, Kenney PA, Merrill MM, Babaian KN, Zhang XY, Maity T, Yang SF, Lin X, Wood CG. Autotaxin-lysophosphatidic acid signaling axis mediates tumorigenesis and development of acquired resistance to sunitinib in renal cell carcinoma. Clin Cancer Res. 2013;19:6461-6472.
65. Bhatt RS, Wang X, Zhang L, Collins MP, Signoretti S, Alsop DC, Goldberg SN, Atkins MB, Mier JW. Renal cancer resistance to antiangiogenic therapy is delayed by restoration of angiostatic signaling. Mol Cancer Ther. 2010;9:2793-2802.
66. Wang X, Zhang L, O'Neill A, Bahamon B, Alsop DC, Mier JW, Goldberg SN, Signoretti S, Atkins MB, Wood CG, Bhatt RS. Cox-2 inhibition enhances the activity of sunitinib in human renal cell carcinoma xenografts. Br J Cancer. 2013;108:319-326.
67. Sato M, Nakai Y, Nakata W, Yoshida T, Hatano K, Kawashima A, Fujita K, Uemura M, Takayama H, Nonomura N. EMMPRIN promotes angiogenesis, proliferation, invasion and resistance to sunitinib in renal cell carcinoma, and its level predicts patient outcome. PLoS One. 2013;8:e74313.
68. Panka DJ, Liu Q, Geissler AK, Mier JW. Effects of HDM2 antagonism on sunitinib resistance, p53 activation, SDF-1 induction, and tumor infiltration by CD11b+/Gr-1+ myeloid derived suppressor cells. Mol Cancer. 2013;12:17.
69. Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski R, Futreal PA, Furge KA, Teh BT. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 2010;70:1063-1071.
70. Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, Rudek MA, Beerepoot LV, Musters RJ, Jansen G, Griffioen AW, Assaraf YG, Pili R, Peters GJ, Verheul HM. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res. 2011;17:7337-7346.
71. Berkers J, Govaere O, Wolter P, Beuselinck B, Schoffski P, van Kempen LC, Albersen M, Van den Oord J, Roskams T, Swinnen J, Joniau S, Van Poppel H, Lerut E. A possible role for microRNA-141 down-regulation in sunitinib resistant metastatic clear cell renal cell carcinoma through induction of epithelial-to-mesenchymal transition and hypoxia resistance. J Urol. 2013;189:1930-1938.
72. Prior C, Perez-Gracia JL, Garcia-Donas J, Rodriguez-Antona C, Guruceaga E, Esteban E, et al. Identification of Tissue microRNAs Predictive of Sunitinib Activity in Patients with Metastatic Renal Cell Carcinoma. PLoS One. 2014;9:e86263.
73. Finke J, Ko J, Rini B, Rayman P, Ireland J, Cohen P. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. International immunopharmacology. 2011;11:856-861.
74. Yu DS, Wu CL, Ping SY, Huang YL, Shen KH. Neutrophil Gelatinase-Associated Lipocalin (NGAL) Can Alternative Mediate Sunitinib Resistance in Renal Cell Carcinoma. J Urol. 2014; doi: 10.1016/j.juro.2013.12.049.
75. Rodriguez-Antona C, Garcia-Donas J. Constitutional genetic variants as predictors of antiangiogenic therapy outcome in renal cell carcinoma. Pharmacogenomics. 2012;13:1621-1633.
76. van der Veldt AA, Eechoute K, Gelderblom H, Gietema J, Guchelaar HJ, van Erp NP, van den Eertwegh AJ, Haanen JB, Mathijssen RH, Wessels JA. Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res. 2011;17:620-629.
77. Garcia-Donas J, Esteban E, Leandro-Garcia LJ, Castellano DE, del AAG, Climent MA, Arranz JA, Gallardo E, Puente J, Bellmunt J, Mellado B, Martínez E, Moreno F, Font A, Robledo M, Rodríguez-Antona C. Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol. 2011;12:1143-1150.
78. Beuselinck B, Karadimou A, Couchy G. A pharmacogenomic scoring system predicting median time to progression (mTTP) on sunitinib (SUN) as first-line treatment in patients (pts) with metastatic renal cell carcinoma (mRCC). Abstarct 359. J Clin Oncol. 2012;30 (Suppl. 5).
79. Bender C, Ullrich A. PRKX, TTBK2 and RSK4 expression causes Sunitinib resistance in kidney carcinoma- and melanoma-cell lines. Int J Cancer. 2012;131:E45-55.
80. Makhov PB, Golovine K, Kutikov A, Teper E, Canter DJ, Simhan J, Uzzo RG, Kolenko VM. Modulation of Akt/mTOR signaling overcomes sunitinib resistance in renal and prostate cancer cells. Mol Cancer Ther. 2012;11:1510-517.
81. Singhal SS, Sehrawat A, Sahu M, Singhal P, Vatsyayan R, Rao Lelsani PC, Yadav S, Awasthi S. Rlip76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer. Int J Cancer. 2010;126:1327-1338.
82. Gao H, Deng L. Sphingosine Kinase-1 Activation Causes Acquired Resistance Against Sunitinib in Renal Cell Carcinoma Cells. Cell Biochem Biophys. 2013;68:419-425.
83. Gonzalez LJL, Espinosa E, Garcia CI, Garcia-Donas J, Lopez M, Meana A, Puente J, Bellmunt J. Sequential therapy in metastatic renal cell carcinoma: pre-clinical and clinical rationale for selecting a second- or subsequent-line therapy with a different mechanism of action. Cancer Metastasis Rev. 2012;31 Suppl 1:S11-17.
84. Yu JL, Rak JW, Coomber BL, Hicklin DJ, Kerbel RS. Effect of p53 status on tumor response to antiangiogenic therapy. Science. 2002;295:1526-1528.
85. Hammers HJ, Verheul HM, Salumbides B, Sharma R, Rudek M, Jaspers J, Shah P, Ellis L, Shen L, Paesante S, Dykema K, Furge K, Teh BT, Netto G, Pili R. Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study. Mol Cancer Ther. 2010;9:1525-1535.
86. Zama IN, Hutson TE, Elson P, Cleary JM, Choueiri TK, Heng DY, Ramaiya N, Michaelson MD, Garcia JA, Knox JJ, Escudier B, Rini BI. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer. 2010;116:5400-5406.
87. Abe H, Kamai T. Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol. 2013;20:944-955.
88. Cho DC, Atkins MB. Future directions in renal cell carcinoma: 2011 and beyond. Hematol Oncol Clin North Am. 2011;25:917-935.
89. Medioni J, Banu E, Helley D, Scotte F, Fournier L, Mejean A, Chedid A, Azizi M, Andrieu JM, Oudard S. Salvage therapy with bevacizumab-sunitinib combination after failure of sunitinib alone for metastatic renal cell carcinoma: a case series. Eur Urol. 2009;56:207-211.
90. Feldman DR, Baum MS, Ginsberg MS, Hassoun H, Flombaum CD, Velasco S, Fischer P, Ronnen E, Ishill N, Patil S, Motzer RJ. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009; 20;27:1432-1439.
91. Motzer RJ, Hudes G, Wilding G, Schwartz LH, Hariharan S, Kempin S, Fayyad R, Figlin RA. Phase I trial of sunitinib malate plus interferon-alpha for patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2009;7:28-33.
92. Patel PH, Senico PL, Curiel RE, Motzer RJ. Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. 2009;7:24-27.
93. Kroog GS, Feldman DR, Kondagunta GV, Ginsberg MS, Fischer PM, Trinos MJea. Phase I trial of RAD001 (everolimus) plus sunitinib in patients with metastatic renal cell carcinoma (abstract). J Clin Oncol. 2009;27(Suppl):15s.
94. Hutson TE, Bukowski RM, Cowey CL, Figlin R, Escudier B, Sternberg CN. Sequential use of targeted agents in the treatment of renal cell carcinoma. Crit Rev Oncol Hematol. 2011;77:48-62.
95. Sonpavde G, Choueiri TK, Escudier B, Ficarra V, Hutson TE, Mulders PF, Patard JJ, Rini BI, Staehler M, Sternberg CN, Stief CG. Sequencing of agents for metastatic renal cell carcinoma: can we customize therapy? Eur Urol. 2012;61:307-316.
96. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931-1939.
97. Hainsworth JD, Rubin MS, Arrowsmith ER, Khatcheressian J, Crane EJ, Franco LA. Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium Phase II Trial. Clin Genitourin Cancer. 2013;11:270-275.
98. Gupta S, Spiess PE. The prospects of pazopanib in advanced renal cell carcinoma. Ther Adv Urol. 2013;5:223-232.
99. Kumano M, Miyake H, Harada K, Fujisawa M. Sequential use of mammalian target of rapamycin inhibitors in patients with metastatic renal cell carcinoma following failure of tyrosine kinase inhibitors. Med Oncol. 2013;30:745.
100. Sun M, Shariat SF, Trinh QD, Meskawi M, Bianchi M, Hansen J, Abdollah F, Perrotte P, Karakiewicz PI. An evidence-based guide to the selection of sequential therapies in metastatic renal cell carcinoma. Ther Adv Urol. 2013;5:121-128.
101. Raja T. Forty-nine-month survival in a metastatic renal cell carcinoma patient across six lines of targeted therapy. Ecancermedicalscience. 2014;8:406.
2. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456.
3. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124.
4. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061-1068.
5. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427-434.
6. Hudes GR. mTOR as a target for therapy of renal cancer. Clin Adv Hematol Oncol. 2007;5:772-774.
7. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281.
8. Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004;22:4991-5004.
9. Arai E, Kanai Y. Genetic and epigenetic alterations during renal carcinogenesis. Int J Clin Exp Pathol. 2010;4:58-73.
10. Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM, Baylin SB. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A. 1994;91:9700-9704.
11. Clark PE. The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy. Kidney Int. 2009:76:939-945.
12. Pal SK, Quinn DI. Differentiating mTOR inhibitors in renal cell carcinoma. Cancer Treat Rev. 2013;39:709-719.
13. Linehan WM, Vasselli J, Srinivasan R, Walther MM, Merino M, Choyke P, Vocke C, Schmidt L, Isaacs JS, Glenn G, Toro J, Zbar B, Bottaro D, Neckers L. Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res. 2004;10(18 Pt 2):6282S-6289S.
14. Morais C, Johnson DW, Gobe GC. The VHL-HIF signaling in renal cell carcinoma: Promises and pitfalls. In: Amato RJ (Ed). Emerging Research and Treatments in Renal Cell Carcinoma. InTech Publishers, Coratia 2011; p. 57-82.
15. Huang LE, Bunn HF. Hypoxia-inducible factor and its biomedical relevance. J Biol Chem. 2003;278:19575-19578.
16. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271-275.
17. Maynard MA, Ohh M. Von Hippel-Lindau tumor suppressor protein and hypoxia-inducible factor in kidney cancer. Am J Nephrol. 2004;24:1-13.
18. Baldewijns MM, van Vlodrop IJ, Vermeulen PB, Soetekouw PM, van Engeland M, de Bruine AP. VHL and HIF signalling in renal cell carcinogenesis. J Pathol. 2010;221:125-138.
19. Maynard MA, Qi H, Chung J, Lee EH, Kondo Y, Hara S, et al. Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem. 2003;278:11032-11040.
20. Stebbins CE, Kaelin WG, Jr., Pavletich NP. Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science. 1999;284:455-461.
21. Kaelin WG. The von Hippel-Lindau tumor suppressor protein: roles in cancer and oxygen sensing. Cold Spring Harb Symp Quant Biol. 2005;70:159-166.
22. Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. Embo J. 2000;19:4298-4309.
23. Salceda S, Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem. 1997;272:22642-22647.
24. Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology (Williston Park). 2005;69 Suppl 3:4-10.
25. Cebe-Suarez S, Zehnder-Fjallman A, Ballmer-Hofer K. The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci. 2006;63:601-615.
26. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011-1027.
27. Roy H, Bhardwaj S, Yla-Herttuala S. Biology of vascular endothelial growth factors. FEBS Lett. 2006;580:2879-2887.
28. Stuttfeld E, Ballmer-Hofer K. Structure and function of VEGF receptors. IUBMB Life. 2009;61:915-922.
29. Tammela T, Enholm B, Alitalo K, Paavonen K. The biology of vascular endothelial growth factors. Cardiovasc Res. 2005;65:550-563.
30. Thurston G, Kitajewski J. VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis. Br J Cancer. 2008;99:1204-1209.
31. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol. 2006;7:359-371.
32. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6:389-395.
33. Hellstrom M, Kalen M, Lindahl P, Abramsson A, Betsholtz C. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development. 1999;126:3047-3055.
34. Labrecque L, Lamy S, Chapus A, Mihoubi S, Durocher Y, Cass B, Bojanowski MW, Gingras D, Béliveau R. Combined inhibition of PDGF and VEGF receptors by ellagic acid, a dietary-derived phenolic compound. Carcinogenesis. 2005;26:821-826.
35. Ostman A. PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev. 2004;15:275-286.
36. Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27:2278-2287.
37. Populo H, Lopes JM, Soares P. The mTOR Signalling Pathway in Human Cancer. Int J Mol Sci. 2012;13:1886-1918.
38. Kucejova B, Pena-Llopis S, Yamasaki T, Sivanand S, Tran TA, Alexander S, Alexander S, Wolff NC, Lotan Y, Xie XJ, Kabbani W, Kapur P, Brugarolas J. Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma. Mol Cancer Res. 2011;9:1255-1265.
39. Weichhart T. Mammalian target of rapamycin: a signaling kinase for every aspect of cellular life. Methods Mol Biol. 2012;821:1-14.
40. Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:125-127.
41. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355:1345-1356.
42. Linehan WM, Bratslavsky G, Pinto PA, Schmidt LS, Neckers L, Bottaro DP, Srinivasan R. Molecular diagnosis and therapy of kidney cancer. Annu Rev Med. 2010;61:329-343.
43. Gomez-Pinillos A, Ferrari AC. mTOR signaling pathway and mTOR inhibitors in cancer therapy. Hematol Oncol Clin North Am. 2012;26:483-505.
44. Figlin RA, Kaufmann I, Brechbiel J. Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: new strategies for overcoming resistance to VEGFR and mTORC1 inhibitors. Int J Cancer. 2013;133:788-796.
45. Zhou H, Huang S. Role of mTOR signaling in tumor cell motility, invasion and metastasis. Curr Protein Pept Sci. 2011;12:30-42.
46. Banumathy G, Cairns P. Signaling pathways in renal cell carcinoma. Cancer Biol Ther. 2010;10:658-664.
47. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8:579-591.
48. Ainsworth NL, Lee JS, Eisen T. Impact of anti-angiogenic treatments on metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2009;9:1793-1805.
49. Zhou H, Luo Y, Huang S. Updates of mTOR inhibitors. Anticancer Agents Med Chem. 2010;10:571-581.
50. Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res. 2006;66:5549-5554.
51. Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, Booth BP, Verbois SL, Morse DE, Liang CY, Chidambaram N, Jiang JX, Tang S, Mahjoob K, Justice R, Pazdur R. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13:1367-1373.
52. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:16-24.
53. Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD. Sunitinib in patients with metastatic renal cell carcinoma. Jama. 2006;295:2516-2524.
54. Britten CD, Kabbinavar F, Hecht JR, Bello CL, Li J, Baum C, Slamon D. A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period. Cancer Chemother Pharmacol. 2008;61:515-524.
55. Dutcher JP. Recent developments in the treatment of renal cell carcinoma. Ther Adv Urol. 2013;5:338-353.
56. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10:992-1000.
57. Porta C, Sabbatini R, Procopio G, Paglino C, Galligioni E, Ortega C. Primary resistance to tyrosine kinase inhibitors in patients with advanced renal cell carcinoma: state-of-the-science. Expert Rev Anticancer Ther. 2012;12:1571-1577.
58. Heng DY, Mackenzie MJ, Vaishampayan UN, Bjarnason GA, Knox JJ, Tan MH, Wood L, Wang Y, Kollmannsberger C, North S, Donskov F, Rini BI, Choueiri TK.. Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy. Ann Oncol. 2012;23:1549-1555.
59. Busch J, Seidel C, Weikert S, Wolff I, Kempkensteffen C, Weinkauf L, Hinz S, Magheli A, Miller K, Grünwald V. Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma. BMC Cancer. 2011;11:295.
60. Santos N, Wenger JB, Havre P, Liu Y, Dagan R, Imanirad I, Ivey AM, Zlotecki RA, Algood CB, Gilbert SM, Allegra CJ, Okunieff P, Vieweg J, Dang NH, Luesch H, Dang LH. Combination therapy for renal cell cancer: what are possible options? Oncology. 2011;81:220-229.
61. Ravaud A, Gross-Goupil M. Overcoming resistance to tyrosine kinase inhibitors in renal cell carcinoma. Cancer Treat Rev. 2012;38:996-1003.
62. Rini BI, Flaherty K. Clinical effect and future considerations for molecularly-targeted therapy in renal cell carcinoma. Urol Oncol. 2008;26:543-549
63. Simon T, Gobe G, Wu C, Ko F, C. M. Molecular mechanisms of sunitinib resistance in renal cell carcinoma. In: Morais C (Ed). Advances in drug resistance research. Nova Science Publishers, Inc. NY, USA; 2014. p. 225-245.
64. Su SC, Hu X, Kenney PA, Merrill MM, Babaian KN, Zhang XY, Maity T, Yang SF, Lin X, Wood CG. Autotaxin-lysophosphatidic acid signaling axis mediates tumorigenesis and development of acquired resistance to sunitinib in renal cell carcinoma. Clin Cancer Res. 2013;19:6461-6472.
65. Bhatt RS, Wang X, Zhang L, Collins MP, Signoretti S, Alsop DC, Goldberg SN, Atkins MB, Mier JW. Renal cancer resistance to antiangiogenic therapy is delayed by restoration of angiostatic signaling. Mol Cancer Ther. 2010;9:2793-2802.
66. Wang X, Zhang L, O'Neill A, Bahamon B, Alsop DC, Mier JW, Goldberg SN, Signoretti S, Atkins MB, Wood CG, Bhatt RS. Cox-2 inhibition enhances the activity of sunitinib in human renal cell carcinoma xenografts. Br J Cancer. 2013;108:319-326.
67. Sato M, Nakai Y, Nakata W, Yoshida T, Hatano K, Kawashima A, Fujita K, Uemura M, Takayama H, Nonomura N. EMMPRIN promotes angiogenesis, proliferation, invasion and resistance to sunitinib in renal cell carcinoma, and its level predicts patient outcome. PLoS One. 2013;8:e74313.
68. Panka DJ, Liu Q, Geissler AK, Mier JW. Effects of HDM2 antagonism on sunitinib resistance, p53 activation, SDF-1 induction, and tumor infiltration by CD11b+/Gr-1+ myeloid derived suppressor cells. Mol Cancer. 2013;12:17.
69. Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski R, Futreal PA, Furge KA, Teh BT. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 2010;70:1063-1071.
70. Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, Rudek MA, Beerepoot LV, Musters RJ, Jansen G, Griffioen AW, Assaraf YG, Pili R, Peters GJ, Verheul HM. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res. 2011;17:7337-7346.
71. Berkers J, Govaere O, Wolter P, Beuselinck B, Schoffski P, van Kempen LC, Albersen M, Van den Oord J, Roskams T, Swinnen J, Joniau S, Van Poppel H, Lerut E. A possible role for microRNA-141 down-regulation in sunitinib resistant metastatic clear cell renal cell carcinoma through induction of epithelial-to-mesenchymal transition and hypoxia resistance. J Urol. 2013;189:1930-1938.
72. Prior C, Perez-Gracia JL, Garcia-Donas J, Rodriguez-Antona C, Guruceaga E, Esteban E, et al. Identification of Tissue microRNAs Predictive of Sunitinib Activity in Patients with Metastatic Renal Cell Carcinoma. PLoS One. 2014;9:e86263.
73. Finke J, Ko J, Rini B, Rayman P, Ireland J, Cohen P. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. International immunopharmacology. 2011;11:856-861.
74. Yu DS, Wu CL, Ping SY, Huang YL, Shen KH. Neutrophil Gelatinase-Associated Lipocalin (NGAL) Can Alternative Mediate Sunitinib Resistance in Renal Cell Carcinoma. J Urol. 2014; doi: 10.1016/j.juro.2013.12.049.
75. Rodriguez-Antona C, Garcia-Donas J. Constitutional genetic variants as predictors of antiangiogenic therapy outcome in renal cell carcinoma. Pharmacogenomics. 2012;13:1621-1633.
76. van der Veldt AA, Eechoute K, Gelderblom H, Gietema J, Guchelaar HJ, van Erp NP, van den Eertwegh AJ, Haanen JB, Mathijssen RH, Wessels JA. Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res. 2011;17:620-629.
77. Garcia-Donas J, Esteban E, Leandro-Garcia LJ, Castellano DE, del AAG, Climent MA, Arranz JA, Gallardo E, Puente J, Bellmunt J, Mellado B, Martínez E, Moreno F, Font A, Robledo M, Rodríguez-Antona C. Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol. 2011;12:1143-1150.
78. Beuselinck B, Karadimou A, Couchy G. A pharmacogenomic scoring system predicting median time to progression (mTTP) on sunitinib (SUN) as first-line treatment in patients (pts) with metastatic renal cell carcinoma (mRCC). Abstarct 359. J Clin Oncol. 2012;30 (Suppl. 5).
79. Bender C, Ullrich A. PRKX, TTBK2 and RSK4 expression causes Sunitinib resistance in kidney carcinoma- and melanoma-cell lines. Int J Cancer. 2012;131:E45-55.
80. Makhov PB, Golovine K, Kutikov A, Teper E, Canter DJ, Simhan J, Uzzo RG, Kolenko VM. Modulation of Akt/mTOR signaling overcomes sunitinib resistance in renal and prostate cancer cells. Mol Cancer Ther. 2012;11:1510-517.
81. Singhal SS, Sehrawat A, Sahu M, Singhal P, Vatsyayan R, Rao Lelsani PC, Yadav S, Awasthi S. Rlip76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer. Int J Cancer. 2010;126:1327-1338.
82. Gao H, Deng L. Sphingosine Kinase-1 Activation Causes Acquired Resistance Against Sunitinib in Renal Cell Carcinoma Cells. Cell Biochem Biophys. 2013;68:419-425.
83. Gonzalez LJL, Espinosa E, Garcia CI, Garcia-Donas J, Lopez M, Meana A, Puente J, Bellmunt J. Sequential therapy in metastatic renal cell carcinoma: pre-clinical and clinical rationale for selecting a second- or subsequent-line therapy with a different mechanism of action. Cancer Metastasis Rev. 2012;31 Suppl 1:S11-17.
84. Yu JL, Rak JW, Coomber BL, Hicklin DJ, Kerbel RS. Effect of p53 status on tumor response to antiangiogenic therapy. Science. 2002;295:1526-1528.
85. Hammers HJ, Verheul HM, Salumbides B, Sharma R, Rudek M, Jaspers J, Shah P, Ellis L, Shen L, Paesante S, Dykema K, Furge K, Teh BT, Netto G, Pili R. Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study. Mol Cancer Ther. 2010;9:1525-1535.
86. Zama IN, Hutson TE, Elson P, Cleary JM, Choueiri TK, Heng DY, Ramaiya N, Michaelson MD, Garcia JA, Knox JJ, Escudier B, Rini BI. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer. 2010;116:5400-5406.
87. Abe H, Kamai T. Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol. 2013;20:944-955.
88. Cho DC, Atkins MB. Future directions in renal cell carcinoma: 2011 and beyond. Hematol Oncol Clin North Am. 2011;25:917-935.
89. Medioni J, Banu E, Helley D, Scotte F, Fournier L, Mejean A, Chedid A, Azizi M, Andrieu JM, Oudard S. Salvage therapy with bevacizumab-sunitinib combination after failure of sunitinib alone for metastatic renal cell carcinoma: a case series. Eur Urol. 2009;56:207-211.
90. Feldman DR, Baum MS, Ginsberg MS, Hassoun H, Flombaum CD, Velasco S, Fischer P, Ronnen E, Ishill N, Patil S, Motzer RJ. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009; 20;27:1432-1439.
91. Motzer RJ, Hudes G, Wilding G, Schwartz LH, Hariharan S, Kempin S, Fayyad R, Figlin RA. Phase I trial of sunitinib malate plus interferon-alpha for patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2009;7:28-33.
92. Patel PH, Senico PL, Curiel RE, Motzer RJ. Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. 2009;7:24-27.
93. Kroog GS, Feldman DR, Kondagunta GV, Ginsberg MS, Fischer PM, Trinos MJea. Phase I trial of RAD001 (everolimus) plus sunitinib in patients with metastatic renal cell carcinoma (abstract). J Clin Oncol. 2009;27(Suppl):15s.
94. Hutson TE, Bukowski RM, Cowey CL, Figlin R, Escudier B, Sternberg CN. Sequential use of targeted agents in the treatment of renal cell carcinoma. Crit Rev Oncol Hematol. 2011;77:48-62.
95. Sonpavde G, Choueiri TK, Escudier B, Ficarra V, Hutson TE, Mulders PF, Patard JJ, Rini BI, Staehler M, Sternberg CN, Stief CG. Sequencing of agents for metastatic renal cell carcinoma: can we customize therapy? Eur Urol. 2012;61:307-316.
96. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931-1939.
97. Hainsworth JD, Rubin MS, Arrowsmith ER, Khatcheressian J, Crane EJ, Franco LA. Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium Phase II Trial. Clin Genitourin Cancer. 2013;11:270-275.
98. Gupta S, Spiess PE. The prospects of pazopanib in advanced renal cell carcinoma. Ther Adv Urol. 2013;5:223-232.
99. Kumano M, Miyake H, Harada K, Fujisawa M. Sequential use of mammalian target of rapamycin inhibitors in patients with metastatic renal cell carcinoma following failure of tyrosine kinase inhibitors. Med Oncol. 2013;30:745.
100. Sun M, Shariat SF, Trinh QD, Meskawi M, Bianchi M, Hansen J, Abdollah F, Perrotte P, Karakiewicz PI. An evidence-based guide to the selection of sequential therapies in metastatic renal cell carcinoma. Ther Adv Urol. 2013;5:121-128.
101. Raja T. Forty-nine-month survival in a metastatic renal cell carcinoma patient across six lines of targeted therapy. Ecancermedicalscience. 2014;8:406.
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Sunitinib resistance in renal cell carcinoma. (2014). Journal of Kidney Cancer, 1(1), 1-11. https://doi.org/10.15586/jkcvhl.2014.7
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Kidney Cancer: Review Articles
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How to Cite
Sunitinib resistance in renal cell carcinoma. (2014). Journal of Kidney Cancer, 1(1), 1-11. https://doi.org/10.15586/jkcvhl.2014.7