title: Strategies to overcome therapeutic resistance in renal cell carcinoma.
abstract: Renal cell cancer (RCC) is a prevalent and lethal disease. At time of diagnosis, most patients present with localized disease. For these patients, the standard of care includes nephrectomy with close monitoring thereafter. While many patients will be cured, 5-year recurrence rates range from 30% to 60%. Furthermore, nearly one-third of patients present with metastatic disease at time of diagnosis. Metastatic disease is rarely curable and typically lethal. Cytotoxic chemotherapy and radiation alone are incapable of controlling the disease. Extensive effort was expended in the development of cytokine therapies but response rates remain low. Newer agents targeting angiogenesis and mTOR signaling emerged in the 2000s and revolutionized patient care. While these agents improve progression free survival, the development of resistance is nearly universal. A new era of immunotherapy is now emerging, led by the checkpoint inhibitors. However, therapeutic resistance remains a complex issue that is likely to persist.
  
  
  
  In this review, we systematically evaluate preclinical research and clinical trials that address resistance to the primary RCC therapies, including anti-angiogenesis agents, mTOR inhibitors, and immunotherapies. As clear cell RCC is the most common adult kidney cancer and has been the focus of most studies, it will be the focus of this review.
authors.affiliation: Departments of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, 2220 Pierce Ave, PRB 646, Nashville, TN 37232. TEL: (615) 936-2003; FAX: (615) 343-7602. Peter.Siska@Vanderbilt.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Siska
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, PRB 646, Nashville, TN 37232. TEL: (615) 936-2003; FAX: (615) 343-7602. Katy.Beckermann@Vanderbilt.edu.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Beckermann
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, PRB 777, Nashville, TN 37232. TEL: (615) 322-4967; FAX: (615) 343-7602. Kimryn.Rathmell@Vanderbilt.edu.
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, PRB 777, Nashville, TN 37232. TEL: (615) 322-4967; FAX: (615) 343-7602. Scott.M.Haake@Vanderbilt.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Haake
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D002986:Clinical Trials as Topic; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000037:antagonists & inhibitors; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D007680:Kidney Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D009392:Nephrectomy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D061025:Costimulatory and Inhibitory T-Cell Receptors; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D058570:TOR Serine-Threonine Kinases
keywords: Angiogenesis; Immunotherapy; Renal cell carcinoma; Resistance; mTOR