title: Resistance of renal cell carcinoma to sorafenib is mediated by potentially reversible gene expression.
abstract: OBJECTIVE
  Resistance to antiangiogenic therapy is an important clinical problem. We examined whether resistance occurs at least in part via reversible, physiologic changes in the tumor, or results solely from stable genetic changes in resistant tumor cells.
  
  
  METHODS
  Mice bearing two human RCC xenografts were treated with sorafenib until they acquired resistance. Resistant 786-O cells were harvested and reimplanted into naïve mice. Mice bearing resistant A498 cells were subjected to a 1 week treatment break. Sorafenib was then again administered to both sets of mice. Tumor growth patterns, gene expression, viability, blood vessel density, and perfusion were serially assessed in treated vs control mice.
  
  
  RESULTS
  Despite prior resistance, reimplanted 786-O tumors maintained their ability to stabilize on sorafenib in sequential reimplantation steps. A transcriptome profile of the tumors revealed that the gene expression profile of tumors upon reimplantation reapproximated that of the untreated tumors and was distinct from tumors exhibiting resistance to sorafenib. In A498 tumors, revascularization was noted with resistance and cessation of sorafenib therapy and tumor perfusion was reduced and tumor cell necrosis enhanced with re-exposure to sorafenib.
  
  
  CONCLUSIONS
  In two RCC cell lines, resistance to sorafenib appears to be reversible. These results support the hypothesis that resistance to VEGF pathway therapy is not solely the result of a permanent genetic change in the tumor or selection of resistant clones, but rather is due to a great extent to reversible changes that likely occur in the tumor and/or its microenvironment.
authors.affiliation: Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Manoj
authors.initials: M
authors.lastname: Bhasin
authors.forename: Rachel
authors.initials: R
authors.lastname: Schor-Bardach
authors.forename: Xiaoen
authors.initials: X
authors.lastname: Wang
authors.forename: Michael P
authors.initials: MP
authors.lastname: Collins
authors.forename: David
authors.initials: D
authors.lastname: Panka
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Putheti
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: David C
authors.initials: DC
authors.lastname: Alsop
authors.forename: Towia
authors.initials: T
authors.lastname: Libermann
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
authors.forename: S Nahum
authors.initials: SN
authors.lastname: Goldberg
authors.forename: Rupal S
authors.initials: RS
authors.lastname: Bhatt
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib