title: Synergistic inhibition of thyroid cancer by suppressing MAPK/PI3K/AKT pathways.
abstract: BACKGROUND
  Although a wide spectrum of inhibitors of the MEK/ERK and PI3K/AKT pathways have been discovered and entered clinical trials, the effects of their individual use in thyroid cancer were often disappointing. We hypothesized that dual targeting of these two pathways would be a safe and effective strategy against aggressive thyroid cancers.
  
  
  METHODS
  We examined the antiproliferative effects of the MEK/ERK inhibitor AZD6244 and the PI3K/AKT inhibitor GDC0941, individually or in combination, on thyroid cancer cells harboring both the BRAF(V600E) and PIK3CA mutations. The effects of drug exposure on both total and phosphorylated (p-) forms of AKT and ERK were monitored by Western blotting analysis. Effects of these inhibitors on cell-cycle progression and apoptosis were measured by flow cytometry and DNA-fragmentation analyses, respectively.
  
  
  RESULTS
  We observed significant toxicities to viability of cells with low concentrations of AZD6244 or GDC0941, which were synergistic when the two inhibitors were used in combination (P < 0.01). AZD6244 abrogated p-ERK and GDC0941 abrogated p-AKT levels, confirming their expected target effects. Unexpectedly, monotherapy with AZD6244 resulted in activation of the PI3K signaling pathway in some cancer cell lines and co-exposure to AZD6244 and GDC0941 was necessary to suppress both pathways. Flow cytometry showed G1 arrest. DNA fragmentation analysis showed an increased apoptosis of cells dually treated with the two inhibitors.
  
  
  CONCLUSIONS
  Concomitant suppression of MEK/ERK and PI3K/AKT pathways by AZD6244 and GDC0941 abrogates compensatory mechanisms of tumor survival and causes synergistic cytotoxicity in thyroid cancer cells.
authors.affiliation: Department of Surgery, Tulane University School of Medicine, New Orleans, Louisiana; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Emad
authors.initials: E
authors.lastname: Kandil
authors.forename: Koji
authors.initials: K
authors.lastname: Tsumagari
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ma
authors.forename: Zakaria Y
authors.initials: ZY
authors.lastname: Abd Elmageed
authors.forename: Xinying
authors.initials: X
authors.lastname: Li
authors.forename: Douglas
authors.initials: D
authors.lastname: Slakey
authors.forename: Debasis
authors.initials: D
authors.lastname: Mondal
authors.forename: Asim B
authors.initials: AB
authors.lastname: Abdel-Mageed
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002291:Carcinoma, Papillary; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007191:Indazoles; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C517975:AZD 6244
keywords: AZD6244; GDC0941; MAPK; PI3K/AKT; Synergism; Thyroid cancer