title: Strategic combination therapy overcomes tyrosine kinase coactivation in adrenocortical carcinoma.
abstract: BACKGROUND
  Coactivation of tyrosine kinase limits the efficacy of tyrosine kinase inhibitors. We hypothesized that a strategic combination therapy could overcome tyrosine kinase coactivation and compensatory oncogenic signaling in patients with adrenocortical carcinoma (ACC).
  
  
  METHODS
  We profiled 88 tyrosine kinases before and after treatment with sunitinib in H295R and SW13 ACC cells. The effects of monotherapy and strategic combination regimens were determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (ie, MTS) assay.
  
  
  RESULTS
  The minimum inhibitory concentrations (IC(min)) of sunitinib quenched its primary targets: FLT-3, VEGFR-2, and RET. In contrast, ERK, HCK, Chk2, YES, CREB, MEK, MSK, p38, FGR, and AXL were hyperactivated. Monotherapy with sunitinib or PD98059 at their IC(min) reduced proliferation by 23% and 19%, respectively, in H295R cells and by 25% and 24%, respectively, in SW13 cells. Sunitinib and PD98059 in combination decreased proliferation by 68% and 64% in H295R and in SW13 cells, respectively (P < .05 versus monotherapy). The effects of combination treatment exceeded the sum of the effects observed with each individual agent alone.
  
  
  CONCLUSIONS
  We describe the first preclinical model to develop strategic combination therapy to overcome tyrosine kinase coactivation in ACC. Because many tyrosine kinase inhibitors are readily available, this model can be immediately tested in clinical trials for patients with advanced ACC.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Chi-Iou
authors.initials: CI
authors.lastname: Lin
authors.forename: Edward E
authors.initials: EE
authors.lastname: Whang
authors.forename: Jacob
authors.initials: J
authors.lastname: Moalem
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Ruan
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000201:enzymology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005419:Flavonoids / Q000008:administration & dosage*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011758:Pyrroles / Q000008:administration & dosage*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D000077210:Sunitinib
chemical_list: D005419:Flavonoids; D007211:Indoles; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077210:Sunitinib