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. CONCLUSION: 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.
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. CONCLUSION: 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: Erin E Talbert; Jennifer Yang; Thomas A Mace; Matthew R Farren; Alton B Farris; Gregory S Young; Omar Elnaggar; Zheng Che; Cynthia D Timmers; Priyani Rajasekera; Jennifer M Maskarinec; Mark Bloomston; Tanios Bekaii-Saab; Denis C Guttridge; Gregory B Lesinski Journal: Mol Cancer Ther Date: 2016-11-03 Impact factor: 6.261
Authors: William J Gibson; Daniel T Ruan; Vera A Paulson; Justine A Barletta; Glenn J Hanna; Stefan Kraft; Antonio Calles; Matthew A Nehs; Francis D Moore; Amaro Taylor-Weiner; Jeremiah A Wala; Travis I Zack; Thomas C Lee; Fiona M Fennessy; Erik K Alexander; Tom Thomas; Pasi A Janne; Levi A Garraway; Scott L Carter; Rameen Beroukhim; Jochen H Lorch; Eliezer M Van Allen Journal: Clin Cancer Res Date: 2016-10-17 Impact factor: 12.531
Authors: Koji Tsumagari; Zakaria Y Abd Elmageed; Andrew B Sholl; Paul Friedlander; Mohamed Abdraboh; Mingzhao Xing; A Hamid Boulares; Emad Kandil Journal: Cancer Lett Date: 2015-07-21 Impact factor: 8.679
Authors: Koji Tsumagari; Zakaria Y Abd Elmageed; Andrew B Sholl; Erik A Green; Saboori Sobti; Abdul Razzaq Khan; Abdulrahman Kandil; Fadi Murad; Paul Friedlander; A Hamid Boulares; Emad Kandil Journal: Endocr Relat Cancer Date: 2018-01 Impact factor: 5.900
Authors: Romana T Netea-Maier; Viola Klück; Theo S Plantinga; Johannes W A Smit Journal: Front Endocrinol (Lausanne) Date: 2015-02-18 Impact factor: 5.555