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Resistance to Targeted Therapies in Renal Cancer: The Importance of Changing the Mechanism of Action

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Abstract

Renal cell carcinoma (RCC) is a complex disease characterized by mutations in several genes. Loss of function of the von Hippel-Lindau (VHL) tumour suppressor gene is a very common finding in RCC and leads to up-regulation of hypoxia-inducible factor (HIF)-responsive genes accountable for angiogenesis and cell growth, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Binding of these proteins to their cognate tyrosine kinase receptors on endothelial cells promotes angiogenesis. Promotion of angiogenesis is in part due to the activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway. Inhibition of this pathway decreases protein translation and inhibits both angiogenesis and tumour cell proliferation. Although tyrosine kinase inhibitors (TKIs) stand as the main first-line treatment option for advanced RCC, eventually all patients will become resistant to TKIs. Resistance can be overcome by using second-line treatments with different mechanisms of action, such as inhibitors of mTOR, c-MET, programmed death 1 (PD-1) receptor, or the combination of an mTOR inhibitor (mTORi) with a TKI. In this article, we briefly review current evidence regarding mechanisms of resistance in RCC and treatment strategies to overcome resistance with a special focus on the PI3K/AKT/mTOR pathway.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29. doi:10.3322/caac.21254.

    Article  PubMed  Google Scholar 

  2. Bajorin DF. Tumors of the kidney, bladder, ureters, and renal pelvis. In: Goldman L, Schafer AI, editors. Goldman’s Cecil Medicine. 24th ed. Philadelphia, PA: Elsevier Saunders; 2012. p. 1303–8.

    Chapter  Google Scholar 

  3. Gerlinger M, Catto JW, Orntoft TF, Real FX, Zwarthoff EC, Swanton C. Intratumour heterogeneity in urologic cancers: from molecular evidence to clinical implications. Eur Urol. 2015;67(4):729–37. doi:10.1016/j.eururo.2014.04.014.

    Article  CAS  PubMed  Google Scholar 

  4. Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol. 2001;166(5):1611–23. doi:10.1016/S0022-5347(05)65640-6.

    Article  CAS  PubMed  Google Scholar 

  5. Rohrmann K, Staehler M, Haseke N, Bachmann A, Stief CG, Siebels M. Immunotherapy in metastatic renal cell carcinoma. World J Urol. 2005;23(3):196–201. doi:10.1007/s00345-004-0470-4.

    Article  CAS  PubMed  Google Scholar 

  6. Linehan WM, Rubin JS, Bottaro DP. VHL loss of function and its impact on oncogenic signaling networks in clear cell renal cell carcinoma. Int J Biochem Cell Biol. 2009;41(4):753–6. doi:10.1016/j.biocel.2008.09.024.

    Article  CAS  PubMed  Google Scholar 

  7. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039–49. doi:10.1056/NEJMra0706596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005;353(23):2477–90. doi:10.1056/NEJMra043172.

    Article  CAS  PubMed  Google Scholar 

  9. Voss MH, Hsieh JJ, Motzer RJ. Novel approaches targeting the vascular endothelial growth factor axis in renal cell carcinoma. Cancer J. 2013;19(4):299–306. doi:10.1097/PPO.0b013e31829d5cff.

    Article  CAS  PubMed  Google Scholar 

  10. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5(8):671–88. doi:10.1038/nrd2062.

    Article  CAS  PubMed  Google Scholar 

  11. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6(9):729–34. doi:10.1038/nrc1974.

    Article  CAS  PubMed  Google Scholar 

  12. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43–9. doi:10.1038/nature12222.

    Article  CAS  Google Scholar 

  13. Hamid O, Carvajal RD. Anti-programmed death-1 and anti-programmed death-ligand 1 antibodies in cancer therapy. Expert Opin Biol Ther. 2013;13(6):847–61. doi:10.1517/14712598.2013.770836.

    Article  CAS  PubMed  Google Scholar 

  14. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, 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):2103–11. doi:10.1016/S0140-6736(07)61904-7.

    Article  PubMed  Google Scholar 

  15. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803–13. doi:10.1056/NEJMoa1510665.

    Article  CAS  PubMed  Google Scholar 

  16. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–34. doi:10.1056/NEJMoa060655.

    Article  CAS  PubMed  Google Scholar 

  17. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–24. doi:10.1056/NEJMoa065044.

    Article  CAS  PubMed  Google Scholar 

  18. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff 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):1061–8. doi:10.1200/JCO.2009.23.9764.

    Article  CAS  PubMed  Google Scholar 

  19. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931–9. doi:10.1016/S0140-6736(11)61613-9.

    Article  CAS  PubMed  Google Scholar 

  20. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814–23. doi:10.1056/NEJMoa1510016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, et al. Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol. 2012;13(10):1055–62. doi:10.1016/S1470-2045(12)70364-9.

    Article  CAS  PubMed  Google Scholar 

  22. Mulders P, Hawkins R, Nathan P, de Jong I, Osanto S, Porfiri E, et al. Cediranib monotherapy in patients with advanced renal cell carcinoma: results of a randomised phase II study. Eur J Cancer. 2012;48(4):527–37. doi:10.1016/j.ejca.2011.12.022.

    Article  CAS  PubMed  Google Scholar 

  23. Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013;31(30):3791–9. doi:10.1200/JCO.2012.47.4940.

    Article  CAS  PubMed  Google Scholar 

  24. Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(3):286–96. doi:10.1016/S1470-2045(14)70030-0.

    Article  CAS  PubMed  Google Scholar 

  25. Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473–82. doi:10.1016/S1470-2045(15)00290-9.

    Article  CAS  PubMed  Google Scholar 

  26. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271–81. doi:10.1056/NEJMoa066838.

    Article  CAS  PubMed  Google Scholar 

  27. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010;116(18):4256–65. doi:10.1002/cncr.25219.

    Article  CAS  PubMed  Google Scholar 

  28. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer, version 1.2016. http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed October 2015.

  29. European Medicines Agency. Product Information Temsirolimus (Torisel®, Pfizer). http://www.ema.europa.eu/docs/es_ES/document_library/EPAR_-_Product_Information/human/000799/WC500039912.pdf. Accessed October 2015.

  30. European Medicines Agency. Product Information Everolimus (Afinitor®, Novartis). http://www.ema.europa.eu/docs/es_ES/document_library/EPAR_-_Product_Information/human/001038/WC500022814.pdf. Accessed October 2015.

  31. Haddad AQ, Kapur P, Singla N, Raman JD, Then MT, Nuhn P, et al. Validation of mammalian target of rapamycin biomarker panel in patients with clear cell renal cell carcinoma. Cancer. 2015;121(1):43–50. doi:10.1002/cncr.28976.

    Article  CAS  PubMed  Google Scholar 

  32. Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338(6104):221. doi:10.1126/science.1226344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Voss MH, Hakimi AA, Pham CG, Brannon AR, Chen YB, Cunha LF, et al. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin Cancer Res. 2014;20(7):1955–64. doi:10.1158/1078-0432.CCR-13-2345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hsieh J, Chen D, Wang P, Chen Y, Redzematovic A, Marker M et al. Identification of efficacy biomarkers in a large metastatic renal cell carcinoma (mRCC) cohort through next generation sequencing (NGS): Results from RECORD-3. J Clin Oncol. 2015;33(Suppl 15):(Abstract 4509).

  35. Kim JY, Lee SH, Moon KC, Kwak C, Kim HH, Keam B, et al. The Impact of PBRM1 Expression as a Prognostic and Predictive Marker in Metastatic Renal Cell Carcinoma. J Urol. 2015;194(4):1112–9. doi:10.1016/j.juro.2015.04.114.

    Article  CAS  PubMed  Google Scholar 

  36. Brenner W, Farber G, Herget T, Lehr HA, Hengstler JG, Thuroff JW. Loss of tumor suppressor protein PTEN during renal carcinogenesis. Int J Cancer. 2002;99(1):53–7. doi:10.1002/ijc.10303.

    Article  CAS  PubMed  Google Scholar 

  37. Kim HL, Seligson D, Liu X, Janzen N, Bui MH, Yu H, et al. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol. 2005;173(5):1496–501. doi:10.1097/01.ju.0000154351.37249.f0.

    Article  CAS  PubMed  Google Scholar 

  38. Shi Y, Gera J, Hu L, Hsu JH, Bookstein R, Li W, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res. 2002;62(17):5027–34.

    CAS  PubMed  Google Scholar 

  39. Cho D, Signoretti S, Dabora S, Regan M, Seeley A, Mariotti M, et al. Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. 2007;5(6):379–85. doi:10.3816/CGC.2007.n.020.

    Article  CAS  PubMed  Google Scholar 

  40. Li S, Kong Y, Si L, Chi Z, Cui C, Sheng X, et al. Phosphorylation of mTOR and S6RP predicts the efficacy of everolimus in patients with metastatic renal cell carcinoma. BMC Cancer. 2014;14:376. doi:10.1186/1471-2407-14-376.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Park K, Lee JL, Park I, Park S, Ahn Y, Ahn JH, et al. Comparative efficacy of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitor as second-line therapy in patients with metastatic renal cell carcinoma after the failure of first-line VEGF TKI. Med Oncol. 2012;29(5):3291–7. doi:10.1007/s12032-012-0227-7.

    Article  CAS  PubMed  Google Scholar 

  42. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10(10):992–1000. doi:10.1016/S1470-2045(09)70240-2.

    Article  CAS  PubMed  Google Scholar 

  43. Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE, et al. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell. 2008;14(6):435–46. doi:10.1016/j.ccr.2008.10.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8(8):592–603. doi:10.1038/nrc2442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, et al. Expansion of myeloid immune suppressor Gr + CD11b + cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. 2004;6(4):409–21. doi:10.1016/j.ccr.2004.08.031.

    Article  CAS  PubMed  Google Scholar 

  46. Kren L, Valkovsky I, Dolezel J, Capak I, Pacik D, Poprach A, et al. HLA-G and HLA-E specific mRNAs connote opposite prognostic significance in renal cell carcinoma. Diagn Pathol. 2012;7:58. doi:10.1186/1746-1596-7-58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gobe G, Rubin M, Williams G, Sawczuk I, Buttyan R. Apoptosis and expression of Bcl-2, Bcl-XL, and Bax in renal cell carcinomas. Cancer Invest. 2002;20(3):324–32.

    Article  CAS  PubMed  Google Scholar 

  48. Ramp U, Dejosez M, Mahotka C, Czarnotta B, Kalinski T, Wenzel M, et al. Deficient activation of CD95 (APO-1/Fas)-mediated apoptosis: a potential factor of multidrug resistance in human renal cell carcinoma. Br J Cancer. 2000;82(11):1851–9. doi:10.1054/bjoc.2000.1155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Adelaiye R, Ciamporcero E, Miles KM, Sotomayor P, Bard J, Tsompana M, et al. Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with epigenetic modifications. Mol Cancer Ther. 2015;14(2):513–22. doi:10.1158/1535-7163.MCT-14-0208.

    Article  CAS  PubMed  Google Scholar 

  50. Sarkadi B, Homolya L, Szakacs G, Varadi A. Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system. Physiol Rev. 2006;86(4):1179–236. doi:10.1152/physrev.00037.2005.

    Article  CAS  PubMed  Google Scholar 

  51. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2(1):48–58. doi:10.1038/nrc706.

    Article  CAS  PubMed  Google Scholar 

  52. Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, et al. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res. 2011;17(23):7337–46. doi:10.1158/1078-0432.CCR-11-1667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bielecka ZF, Czarnecka AM, Solarek W, Kornakiewicz A, Szczylik C. Mechanisms of Acquired Resistance to Tyrosine Kinase Inhibitors in Clear - Cell Renal Cell Carcinoma (ccRCC). Curr Signal Transduct Ther. 2014;8(3):218–28. doi:10.2174/1574362409666140206223014.

    Article  PubMed  CAS  Google Scholar 

  54. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8(4):299–309. doi:10.1016/j.ccr.2005.09.005.

    Article  CAS  PubMed  Google Scholar 

  55. Welti JC, Gourlaouen M, Powles T, Kudahetti SC, Wilson P, Berney DM, et al. Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib. Oncogene. 2011;30(10):1183–93. doi:10.1038/onc.2010.503.

    Article  CAS  PubMed  Google Scholar 

  56. Martin D, Galisteo R, Gutkind JS. CXCL8/IL8 stimulates vascular endothelial growth factor (VEGF) expression and the autocrine activation of VEGFR2 in endothelial cells by activating NFkappaB through the CBM (Carma3/Bcl10/Malt1) complex. J Biol Chem. 2009;284(10):6038–42. doi:10.1074/jbc.C800207200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Currie MJ, Gunningham SP, Turner K, Han C, Scott PA, Robinson BA, et al. Expression of the angiopoietins and their receptor Tie2 in human renal clear cell carcinomas; regulation by the von Hippel-Lindau gene and hypoxia. J Pathol. 2002;198(4):502–10. doi:10.1002/path.1228.

    Article  CAS  PubMed  Google Scholar 

  58. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997;277(5322):55–60. doi:10.1126/science.277.5322.55.

    Article  CAS  PubMed  Google Scholar 

  59. Loges S, Schmidt T, Carmeliet P. "Antimyeloangiogenic" therapy for cancer by inhibiting PlGF. Clin Cancer Res. 2009;15(11):3648–53. doi:10.1158/1078-0432.CCR-08-2276.

    Article  CAS  PubMed  Google Scholar 

  60. Kim KJ, Cho CS, Kim WU. Role of placenta growth factor in cancer and inflammation. Exp Mol Med. 2012;44(1):10–9. doi:10.3858/emm.2012.44.1.023.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Patel NS, Li JL, Generali D, Poulsom R, Cranston DW, Harris AL. Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res. 2005;65(19):8690–7. doi:10.1158/0008-5472.CAN-05-1208.

    Article  CAS  PubMed  Google Scholar 

  62. Huang QB, Ma X, Li HZ, Ai Q, Liu SW, Zhang Y, et al. Endothelial Delta-like 4 (DLL4) promotes renal cell carcinoma hematogenous metastasis. Oncotarget. 2014;5(10):3066–75. doi:10.18632/oncotarget.1827.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Cuvillier O, Ader I, Bouquerel P, Brizuela L, Malavaud B, Mazerolles C, et al. Activation of sphingosine kinase-1 in cancer: implications for therapeutic targeting. Curr Mol Pharmacol. 2010;3(2):53–65. doi:10.2174/1874467211003020053.

    Article  CAS  PubMed  Google Scholar 

  64. Ader I, Brizuela L, Bouquerel P, Malavaud B, Cuvillier O. Sphingosine kinase 1: a new modulator of hypoxia inducible factor 1alpha during hypoxia in human cancer cells. Cancer Res. 2008;68(20):8635–42. doi:10.1158/0008-5472.CAN-08-0917.

    Article  CAS  PubMed  Google Scholar 

  65. 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(2):125–38. doi:10.1002/path.2689.

    Article  CAS  PubMed  Google Scholar 

  66. Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 2009;23(5):537–48. doi:10.1101/gad.1756509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Edinger AL, Thompson CB. An activated mTOR mutant supports growth factor-independent, nutrient-dependent cell survival. Oncogene. 2004;23(33):5654–63. doi:10.1038/sj.onc.1207738.

    Article  CAS  PubMed  Google Scholar 

  68. Cho DC, Hutson TE, Samlowski W, Sportelli P, Somer B, Richards P, et al. Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy. Cancer. 2012;118(24):6055–62. doi:10.1002/cncr.27668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pantuck AJ, Seligson DB, Klatte T, Yu H, Leppert JT, Moore L, et al. Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer. 2007;109(11):2257–67. doi:10.1002/cncr.22677.

    Article  CAS  PubMed  Google Scholar 

  70. Shojaei F, Ferrara N. Role of the microenvironment in tumor growth and in refractoriness/resistance to anti-angiogenic therapies. Drug Resist Updat. 2008;11(6):219–30. doi:10.1016/j.drup.2008.09.001.

    Article  CAS  PubMed  Google Scholar 

  71. Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 2009;15(1):21–34. doi:10.1016/j.ccr.2008.12.004.

    Article  CAS  PubMed  Google Scholar 

  72. Reinmuth N, Liu W, Jung YD, Ahmad SA, Shaheen RM, Fan F, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J. 2001;15(7):1239–41. doi:10.1096/fj.00-0693fje.

    CAS  PubMed  Google Scholar 

  73. Xian X, Hakansson J, Stahlberg A, Lindblom P, Betsholtz C, Gerhardt H, et al. Pericytes limit tumor cell metastasis. J Clin Invest. 2006;116(3):642–51. doi:10.1172/JCI25705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature. 2007;450(7171):825–31. doi:10.1038/nature06348.

    Article  CAS  PubMed  Google Scholar 

  75. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15(3):220–31. doi:10.1016/j.ccr.2009.01.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Koochekpour S, Jeffers M, Wang PH, Gong C, Taylor GA, Roessler LM, et al. The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999;19(9):5902–12. doi:10.1128/MCB.19.9.5902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Shojaei F, Lee JH, Simmons BH, Wong A, Esparza CO, Plumlee PA, et al. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010;70(24):10090–100. doi:10.1158/0008-5472.CAN-10-0489.

    Article  CAS  PubMed  Google Scholar 

  78. Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell. 2012;22(1):21–35. doi:10.1016/j.ccr.2012.05.037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, et al. Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression. J Cell Physiol. 2007;213(2):374–83. doi:10.1002/jcp.21223.

    Article  CAS  PubMed  Google Scholar 

  80. Arao T, Matsumoto K, Furuta K, Kudo K, Kaneda H, Nagai T, et al. Acquired drug resistance to vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor in human vascular endothelial cells. Anticancer Res. 2011;31(9):2787–96.

    CAS  PubMed  Google Scholar 

  81. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1559–64. doi:10.1126/science.1203543.

    Article  CAS  PubMed  Google Scholar 

  82. Behnsawy HM, Shigemura K, Meligy FY, Yamamichi F, Yamashita M, Haung WC, et al. Possible role of sonic hedgehog and epithelial-mesenchymal transition in renal cell cancer progression. Korean J Urol. 2013;54(8):547–54. doi:10.4111/kju.2013.54.8.547.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Grunwald V, Weikert S, Seidel C, Busch J, Johannsen A, Fenner M, et al. Efficacy of sunitinib re-exposure after failure of an mTOR inhibitor in patients with metastatic RCC. Onkologie. 2011;34(6):310–4. doi:10.1159/000328575.

    Article  PubMed  CAS  Google Scholar 

  84. van der Veldt AA, Eechoute K, Gelderblom H, Gietema J, Guchelaar HJ, van Erp NP, et al. Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res. 2011;17(3):620–9. doi:10.1158/1078-0432.CCR-10-1828.

    Article  PubMed  CAS  Google Scholar 

  85. Beuselinck B, Karadimou A, Lambrechts D, Claes B, Wolter P, Couchy G, et al. Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib. Br J Cancer. 2013;108(4):887–900. doi:10.1038/bjc.2012.548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Garcia-Donas J, Esteban E, Leandro-Garcia LJ, Castellano DE, del Alba AG, Climent MA, et al. 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(12):1143–50. doi:10.1016/S1470-2045(11)70266-2.

    Article  CAS  PubMed  Google Scholar 

  87. 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(1):e86263. doi:10.1371/journal.pone.0086263.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009;27(27):4462–8. doi:10.1200/JCO.2008.21.7034.

    Article  CAS  PubMed  Google Scholar 

  89. Heng DY, Mackenzie MJ, Vaishampayan UN, Bjarnason GA, Knox JJ, Tan MH, et al. Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy. Ann Oncol. 2012;23(6):1549–55. doi:10.1093/annonc/mdr533.

    Article  CAS  PubMed  Google Scholar 

  90. Bridgeman VL, Wan E, Foo S, Nathan MR, Welti JC, Frentzas S, et al. Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma. Mol Cancer Ther. 2016;15(1):172–83. doi:10.1158/1535-7163.MCT-15-0170.

    Article  CAS  PubMed  Google Scholar 

  91. Broekman F, Giovannetti E, Peters GJ. Tyrosine kinase inhibitors: Multi-targeted or single-targeted? World J Clin Oncol. 2011;2(2):80–93. doi:10.5306/wjco.v2.i2.80.

    Article  PubMed  PubMed Central  Google Scholar 

  92. European Medicines Agency. Product Information Sunitinib (Sutent®, Pfizer). http://www.ema.europa.eu/docs/es_ES/document_library/EPAR_-_Product_Information/human/000687/WC500057737.pdf. Accessed October 2015.

  93. European Medicines Agency. Product Information Sorafenib (Nexavar®, Bayer). http://www.ema.europa.eu/docs/es_ES/document_library/EPAR_-_Product_Information/human/000690/WC500027704.pdf. Accessed October 2015.

  94. Sablin MP, Negrier S, Ravaud A, Oudard S, Balleyguier C, Gautier J, et al. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol. 2009;182(1):29–34. doi:10.1016/j.juro.2009.02.119. discussion.

    Article  CAS  PubMed  Google Scholar 

  95. Dudek AZ, Zolnierek J, Dham A, Lindgren BR, Szczylik C. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer. 2009;115(1):61–7. doi:10.1002/cncr.24009.

    Article  CAS  PubMed  Google Scholar 

  96. Di Lorenzo G, Carteni G, Autorino R, Bruni G, Tudini M, Rizzo M, et al. Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol. 2009;27(27):4469–74. doi:10.1200/JCO.2009.22.6480.

    Article  PubMed  Google Scholar 

  97. Garcia JA, Hutson TE, Elson P, Cowey CL, Gilligan T, Nemec C, et al. Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab. Cancer. 2010;116(23):5383–90. doi:10.1002/cncr.25327.

    Article  CAS  PubMed  Google Scholar 

  98. Iacovelli R, Santoni M, Verzoni E, Grassi P, Testa I, de Braud F, et al. Everolimus and temsirolimus are not the same second-line in metastatic renal cell carcinoma. A systematic review and meta-analysis of literature data. Clin Genitourin Cancer. 2015;13(2):137–41. doi:10.1016/j.clgc.2014.07.006.

    Article  PubMed  Google Scholar 

  99. Calvo E, Escudier B, Motzer RJ, Oudard S, Hutson TE, Porta C, et al. Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. Eur J Cancer. 2012;48(3):333–9. doi:10.1016/j.ejca.2011.11.027.

    Article  CAS  PubMed  Google Scholar 

  100. Grunwald V, Karakiewicz PI, Bavbek SE, Miller K, Machiels JP, Lee SH, et al. An international expanded-access programme of everolimus: addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. Eur J Cancer. 2012;48(3):324–32. doi:10.1016/j.ejca.2011.06.054.

    Article  PubMed  CAS  Google Scholar 

  101. Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32(25):2765–72. doi:10.1200/JCO.2013.54.6911.

    Article  CAS  PubMed  Google Scholar 

  102. Motzer R, Alyasova A, Ye D, Karpenko A, Li H, Alekseev B et al. RECORD-4: A multicenter, phase II trial of second-line everolimus (EVE) in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2015;33(Suppl):(Abstract 4518).

  103. Koutsoukos K, Espinosa Montano M, Kontovinis L, Tzannis K, Koutras A, Christodoulou C et al. Everolimus as second-line treatment in metastatic renal cell carcinoma (mRCC) after first-line pazopanib (The RESCUE study): A retrospective analysis by the Hellenic GU Cancer Group (HGUCG) with international collaboration. J Clin Oncol. 2015;33(Suppl):(Abstract e15601).

  104. Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32(8):760–7. doi:10.1200/JCO.2013.50.3961.

    Article  CAS  PubMed  Google Scholar 

  105. Snegovoy A, Varlamov S, Safina S, Varlamov I, Gurina L, Manzyuk LV et al. Everolimus in patients with metastatic renal cell carcinoma (RCC) previously treated with bevacizumab: Final results of prospective multicenter study. J Clin Oncol. 2015;33(Suppl):(Abstract e15621).

  106. Signorovitch J, Pal SK, Reichmann WN, Liu Z, Pérez JR, Vogelzang NJ et al. Comparative effectiveness of everolimus (EVE) and axitinib (AXI) for 2nd targeted therapy (TT) of metastatic renal cell carcinoma (mRCC) in the US: A retrospective chart review. J Clin Oncol. 2015;33(Suppl):(Abstract e15612).

  107. Exelixis Announces Positive Overall Survival Results from METEOR, the Phase 3 Pivotal Trial of Cabozantinib in Advanced Renal Cell Carcinoma. http://ir.exelixis.com/phoenix.zhtml?c=120923&p=irol-newsArticle_print&ID=2133957. Accessed May 2016.

  108. Negrier S, Gravis G, Perol D, Chevreau C, Delva R, Bay JO, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12(7):673–80. doi:10.1016/S1470-2045(11)70124-3.

    Article  CAS  PubMed  Google Scholar 

  109. Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014;32(8):752–9. doi:10.1200/JCO.2013.50.5305.

    Article  CAS  PubMed  Google Scholar 

  110. Flaherty KT, Manola JB, Pins M, McDermott DF, Atkins MB, Dutcher JJ, et al. BEST: A Randomized Phase II Study of Vascular Endothelial Growth Factor, RAF Kinase, and Mammalian Target of Rapamycin Combination Targeted Therapy With Bevacizumab, Sorafenib, and Temsirolimus in Advanced Renal Cell Carcinoma--A Trial of the ECOG-ACRIN Cancer Research Group (E2804). J Clin Oncol. 2015;33(21):2384–91. doi:10.1200/JCO.2015.60.9727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ravaud A, Barrios CH, Alekseev B, Tay MH, Agarwala SS, Yalcin S, et al. RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon alpha-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma. Ann Oncol. 2015;26(7):1378–84. doi:10.1093/annonc/mdv170.

    CAS  PubMed  Google Scholar 

  112. Hainsworth JD, Spigel DR, Burris 3rd HA, Waterhouse D, Clark BL, Phase WR, et al. trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J Clin Oncol. 2010;28(13):2131–6. doi:10.1200/JCO.2009.26.3152.

    Article  CAS  PubMed  Google Scholar 

  113. Medioni J, Banu E, Helley D, Scotte F, Fournier L, Mejean A, et al. Salvage therapy with bevacizumab-sunitinib combination after failure of sunitinib alone for metastatic renal cell carcinoma: a case series. Eur Urol. 2009;56(1):207–11. doi:10.1016/j.eururo.2009.01.001.

    Article  CAS  PubMed  Google Scholar 

  114. Rasmussen N, Rathmell WK. Looking beyond inhibition of VEGF/mTOR: emerging targets for renal cell carcinoma drug development. Curr Clin Pharmacol. 2011;6(3):199–206. doi:10.2174/157488411797189389.

    Article  CAS  PubMed  Google Scholar 

  115. Milella M, Felici A. Biology of metastatic renal cell carcinoma. J Cancer. 2011;2:369–73. doi:10.7150/jca.2.369.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Lorenz MC, Heitman J. TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin. J Biol Chem. 1995;270(46):27531–7. doi:10.1074/jbc.270.46.27531.

    Article  CAS  PubMed  Google Scholar 

  117. Kucejova B, Pena-Llopis S, Yamasaki T, Sivanand S, Tran TA, Alexander S, et al. Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma. Mol Cancer Res. 2011;9(9):1255–65. doi:10.1158/1541-7786.MCR-11-0302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Harada K, Miyake H, Kumano M, Fujisawa M. Acquired resistance to temsirolimus in human renal cell carcinoma cells is mediated by the constitutive activation of signal transduction pathways through mTORC2. Br J Cancer. 2013;109(9):2389–95. doi:10.1038/bjc.2013.602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Juengel E, Dauselt A, Makarevic J, Wiesner C, Tsaur I, Bartsch G, et al. Acetylation of histone H3 prevents resistance development caused by chronic mTOR inhibition in renal cell carcinoma cells. Cancer Lett. 2012;324(1):83–90. doi:10.1016/j.canlet.2012.05.003.

    Article  CAS  PubMed  Google Scholar 

  120. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, 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):3065–74. doi:10.1172/JCI34739.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhao Y, Ehara H, Akao Y, Shamoto M, Nakagawa Y, Banno Y, et al. Increased activity and intranuclear expression of phospholipase D2 in human renal cancer. Biochem Biophys Res Commun. 2000;278(1):140–3. doi:10.1006/bbrc.2000.3719.

    Article  CAS  PubMed  Google Scholar 

  122. Hammerman PS, Fox CJ, Birnbaum MJ, Thompson CB. Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival. Blood. 2005;105(11):4477–83. doi:10.1182/blood-2004-09-3706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhang F, Beharry ZM, Harris TE, Lilly MB, Smith CD, Mahajan S, et al. PIM1 protein kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells. Cancer Biol Ther. 2009;8(9):846–53.

    Article  CAS  PubMed  Google Scholar 

  124. Dilling MB, Germain GS, Dudkin L, Jayaraman AL, Zhang X, Harwood FC, et al. 4E-binding proteins, the suppressors of eukaryotic initiation factor 4E, are down-regulated in cells with acquired or intrinsic resistance to rapamycin. J Biol Chem. 2002;277(16):13907–17. doi:10.1074/jbc.M110782200.

    Article  CAS  PubMed  Google Scholar 

  125. Graff JR, Konicek BW, Carter JH, Marcusson EG. Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res. 2008;68(3):631–4. doi:10.1158/0008-5472.CAN-07-5635.

    Article  CAS  PubMed  Google Scholar 

  126. Luo Y, Marx SO, Kiyokawa H, Koff A, Massague J, Marks AR. Rapamycin resistance tied to defective regulation of p27Kip1. Mol Cell Biol. 1996;16(12):6744–51. doi:10.1128/MCB.16.12.6744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Yu K, Toral-Barza L, Shi C, Zhang WG, Lucas J, Shor B, et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res. 2009;69(15):6232–40. doi:10.1158/0008-5472.CAN-09-0299.

    Article  CAS  PubMed  Google Scholar 

  128. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009;284(12):8023–32. doi:10.1074/jbc.M900301200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010;70(1):288–98. doi:10.1158/0008-5472.CAN-09-1751.

    Article  CAS  PubMed  Google Scholar 

  130. Rodrik-Outmezguine VS, Okaniwa M, Yao Z, Novotny CJ, McWhirter C, Banaji A, et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016;534(7606):272–6. doi:10.1038/nature17963.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Thomas HE, Mercer CA, Carnevalli LS, Park J, Andersen JB, Conner EA, et al. mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma. Sci Transl Med. 2012;4(139):139ra84. doi:10.1126/scitranslmed.3003923.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Carlo MI, Molina AM, Lakhman Y, Patil S, Woo K, DeLuca J, et al. A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma. Oncologist. 2016;21(7):787–8. doi:10.1634/theoncologist.2016-0145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Di Lorenzo G, Buonerba C, Federico P, Rescigno P, Milella M, Ortega C, et al. Third-line sorafenib after sequential therapy with sunitinib and mTOR inhibitors in metastatic renal cell carcinoma. Eur Urol. 2010;58(6):906–11. doi:10.1016/j.eururo.2010.09.008.

    Article  PubMed  CAS  Google Scholar 

  134. Grunwald V, Seidel C, Fenner M, Ganser A, Busch J, Weikert S. Treatment of everolimus-resistant metastatic renal cell carcinoma with VEGF-targeted therapies. Br J Cancer. 2011;105(11):1635–9. doi:10.1038/bjc.2011.389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Porta C, Paglino C, Procopio G, Sabbatini R, Bellmunt J, Schmidinger M et al. Optimizing the sequential treatment of metastatic renal cell carcinoma (mRCC)—a retrospective, multicenter, analysis of 40 patients treated with either Sorafenib, an mTOR inhibitor (mTORI) and Sunitinib, or Sunitinib, an mTORI and Sorafenib. Eur J Cancer. 2011;47(Suppl 1):(Abstract 7131).

  136. Blesius A, Beuselinck B, Chevreau C, Ravaud A, Rolland F, Oudard S, et al. Are tyrosine kinase inhibitors still active in patients with metastatic renal cell carcinoma previously treated with a tyrosine kinase inhibitor and everolimus? Experience of 36 patients treated in France in the RECORD-1 Trial. Clin Genitourin Cancer. 2013;11(2):128–33. doi:10.1016/j.clgc.2012.12.001.

    Article  PubMed  Google Scholar 

  137. Oudard S, Gross-Goupil M, Geoffrois L, Guillot A, Chevreau C, Deville JL et al., editors. Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma (mRCC) - Results of the RESUME study. ESMO 2014; 29th September; Madrid, Spain.

  138. Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol. 2008;26(3):361–7. doi:10.1200/JCO.2007.12.0345.

    Article  CAS  PubMed  Google Scholar 

  139. Powles T, Wheater M, Din O, Geldart T, Boleti E, Stockdale A, et al. A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer. Eur Urol. 2016;69(3):450–6. doi:10.1016/j.eururo.2015.08.035.

    Article  CAS  PubMed  Google Scholar 

  140. Iacovelli R, Carteni G, Sternberg CN, Milella M, Santoni M, Di Lorenzo G, et al. Clinical outcomes in patients receiving three lines of targeted therapy for metastatic renal cell carcinoma: results from a large patient cohort. Eur J Cancer. 2013;49(9):2134–42. doi:10.1016/j.ejca.2013.02.032.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank Dr. Fernando Sánchez Barbero and Nature Publishing Group Iberoamérica for help in the preparation of the manuscript.

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Authors and Affiliations

  1. Sección de Oncología Médica, Hospital Universitario Virgen del Rocío, Sevilla, Spain

    I. Duran

  2. Laboratorio de Terapias Avanzadas y Biomarcadores en Oncología, Instituto de Biomedicina de Sevilla, Sevilla, Spain

    I. Duran

  3. Servicio de Oncología Médica, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain

    J. Lambea

  4. Servicio de Oncología Médica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    P. Maroto

  5. Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain

    J. L. González-Larriba

  6. Novartis Oncology, Barcelona, Spain

    Luis Flores

  7. Servicio de Oncología Médica, Complejo Hospitalario de Jaén, Jaén, Spain

    S. Granados-Principal

  8. GENYO, Centre for Genomics and Oncological Research (Pfizer/University of Granada/Andalusian Regional Government), PTS Granada, Granada, Spain

    S. Granados-Principal

  9. Institut d’Investigació Biomèdica de Bellvitge-IDIBELL, Barcelona, Spain

    M. Graupera

  10. Departmento de Bioquímica, Biología Molecular y Celular, Instituto Universitario de Investigación en Nanociencia de Aragón, Universidad de Zaragoza, Zaragoza, Spain

    B. Sáez

  11. Departamento de Bioquímica y Biología Molecular, Universidad Pompeu Fabra, Barcelona, Spain

    A. Vivancos

  12. ProCURE Research Program, Institut Català d’Oncologia-IDIBELL, L’Hospitalet de Llobregat, Avinguda Gran Via, 199-203, 08907, Barcelona, Spain

    O. Casanovas

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  1. I. Duran
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  5. Luis Flores
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  10. O. Casanovas
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Correspondence to O. Casanovas.

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Novartis provided financial support for medical writing services.

Conflict of Interest

Ignacio Duran has been economically compensated for his assistance to advisory boards from Roche-Genentech, Bristol-Myers Squibb, Exelisis, and Novartis. Julio Lambea has been economically compensated for his assistance to advisory boards and conferences from Novartis and Pfizer. Luis Flores is an employee of Novartis Oncology. Oriol Casanovas has been economically compensated for his assistance to advisory boards and conferences from Novartis, Pfizer, Ipsen, and Teva. The other authors declare no conflict of interest.

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Duran, I., Lambea, J., Maroto, P. et al. Resistance to Targeted Therapies in Renal Cancer: The Importance of Changing the Mechanism of Action. Targ Oncol 12, 19–35 (2017). https://doi.org/10.1007/s11523-016-0463-4

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