title: Specific inhibition of the nuclear exporter exportin-1 attenuates kidney cancer growth.
abstract: OBJECTIVE
  Despite the advent of FDA-approved therapeutics to a limited number of available targets (kinases and mTOR), PFS of kidney cancer (RCC) has been extended only one to two years due to the development of drug resistance. Here, we evaluate a novel therapeutic for RCC which targets the exportin-1 (XPO1) inhibitor.
  
  
  METHODS
  RCC cells were treated with the orally available XPO1 inhibitor, KPT-330, and cell viability and Annexin V (apoptosis) assays, and cell cycle analyses were performed to evaluate the efficacy of KPT-330 in two RCC cell lines. Immunoblotting and immunofluorescence analysis were performed to validate mechanisms of XPO1 inhibition. The efficacy and on-target effects of KPT-330 were further analyzed in vivo in RCC xenograft mice, and KPT-330-resistant cells were established to evaluate potential mechanisms of KPT-330 resistance.
  
  
  RESULTS
  KPT-330 attenuated RCC viability through growth inhibition and apoptosis induction both in vitro and in vivo, a process in which increased nuclear localization of p21 by XPO1 inhibition played a major role. In addition, KPT-330 resistant cells remained sensitive to the currently approved for RCC multi-kinase inhibitors (sunitinib, sorafenib) and mTOR inhibitors (everolimus, temsirolimus), suggesting that these targeted therapeutics would remain useful as second line therapeutics following KPT-330 treatment.
  
  
  CONCLUSIONS
  The orally-available XPO1 inhibitor, KPT-330, represents a novel target for RCC whose in vivo efficacy approaches that of sunitinib. In addition, cells resistant to KPT-330 retain their ability to respond to available RCC therapeutics suggesting a novel approach for treatment in KPT-330-naïve as well as -resistant RCC patients.
authors.affiliation: Division of Nephrology, Dept. of Internal Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Hiromi I
authors.initials: HI
authors.lastname: Wettersten
authors.affiliation: Karyopharm Therapeutics Inc., Natick, Massachusetts, United States of America.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Karyopharm Therapeutics Inc., Natick, Massachusetts, United States of America.
authors.forename: Sharon
authors.initials: S
authors.lastname: Friedlander
authors.affiliation: Karyopharm Therapeutics Inc., Natick, Massachusetts, United States of America.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Karyopharm Therapeutics Inc., Natick, Massachusetts, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.affiliation: Division of Nephrology, Dept. of Internal Medicine, University of California Davis, Davis, California, United States of America; Cancer Center, University of California Davis, Davis, California, United States of America; Medical Service, Sacramento VA Medical Center, Sacramento, California, United States of America.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Weiss
mesh_terms: D021581:Active Transport, Cell Nucleus; D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D017277:Drug Approval; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology; D014481:United States; D014486:United States Food and Drug Administration; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D006834:Hydrazines; D028884:Karyopherins; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C585161:selinexor