title: Selective inhibition of HER2-positive breast cancer cells by the HIV protease inhibitor nelfinavir.
abstract: BACKGROUND
  Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is highly aggressive and has higher risk of recurrence than HER2-negative cancer. With few treatment options available, new drug targets specific for HER2-positive breast cancer are needed.
  
  
  METHODS
  We conducted a pharmacological profiling of seven genotypically distinct breast cancer cell lines using a subset of inhibitors of breast cancer cells from a screen of the Johns Hopkins Drug Library. To identify molecular targets of nelfinavir, identified in the screen as a selective inhibitor of HER2-positive cells, we conducted a genome-wide screen of a haploinsufficiency yeast mutant collection. We evaluated antitumor activity of nelfinavir with xenografts in athymic nude mouse models (n = 4-6 per group) of human breast cancer and repeated mixed-effects regression analysis. All statistical tests were two-sided.
  
  
  RESULTS
  Pharmacological profiling showed that nelfinavir, an anti-HIV drug, selectively inhibited the growth of HER2-positive breast cancer cells in vitro. A genome-wide screening of haploinsufficiency yeast mutants revealed that nelfinavir inhibited heat shock protein 90 (HSP90) function. Further characterization using proteolytic footprinting experiments indicated that nelfinavir inhibited HSP90 in breast cancer cells through a novel mechanism. In vivo, nelfinavir selectively inhibited the growth of HER2-positive breast cancer cells (tumor volume index of HCC1954 cells on day 29, vehicle vs nelfinavir, mean = 14.42 vs 5.16, difference = 9.25, 95% confidence interval [CI] = 5.93 to 12.56, P < .001; tumor volume index of BT474 cells on day 26, vehicle vs nelfinavir, mean = 2.21 vs 0.90, difference = 1.31, 95% CI = 0.83 to 1.78, P < .001). Moreover, nelfinavir inhibited the growth of trastuzumab- and/or lapatinib-resistant, HER2-positive breast cancer cells in vitro at clinically achievable concentrations.
  
  
  CONCLUSIONS
  Nelfinavir was found to be a new class of HSP90 inhibitor and can be brought to HER2-breast cancer treatment trials with the same dosage regimen as that used among HIV patients.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Joong Sup
authors.initials: JS
authors.lastname: Shim
authors.forename: Rajini
authors.initials: R
authors.lastname: Rao
authors.forename: Kristin
authors.initials: K
authors.lastname: Beebe
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: Inkyu
authors.initials: I
authors.lastname: Han
authors.forename: Rita
authors.initials: R
authors.lastname: Nahta
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005455:Fluorescent Antibody Technique; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D019888:Nelfinavir / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000187:drug effects; D012044:Regression Analysis; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017320:HIV Protease Inhibitors; D018841:HSP90 Heat-Shock Proteins; D019888:Nelfinavir; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human