Dual inhibition of RET and FGFR4 restrains medullary thyroid cancer cell growth.
Medullary thyroid cancer is frequently an aggressive form of carcinoma for which there are currently no effective forms of systemic therapy. These carcinomas arise as a result of activating mutations in the RET proto-oncogene transmembrane tyrosine kinase receptor. We, therefore, examined the potential efficacy of the tyrosine kinase inhibitor STI571 on the growth of human TT medullary cancer cells in vitro and in xenografted severe combined immunodeficiency mice. Treatment with STI571 resulted in inhibition of RET phosphorylation, cell proliferation, tumor growth and invasiveness. Based on the profile of expression of fibroblast growth factor receptors (FGFR), we examined the effects of FGFR tyrosine kinase inhibition using the small molecule FGFR inhibitor PD173074. This inhibitor resulted in abrogation of fibroblast growth factor-1-mediated FGFR4 phosphorylation in TT cells, an effect that was accompanied by significant arrest of cell proliferation and tumor growth in vivo. Moreover, the combination of STI571 and PD173074 resulted in greater suppression of cell proliferation in vitro and tumor control in vivo than that achieved with either agent alone. These data highlight RET and FGFR4 as therapeutic targets and suggest a potential role for the combined use of tyrosine kinase inhibitors in the management of inoperable medullary thyroid cancers.
Ezzat
Shereen
S
Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.
Huang
Ping
P
Dackiw
Alan
A
Asa
Sylvia L
SL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D018276:Carcinoma, Medullary / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000473:pathology / Q000517:prevention & control*; D023041:Xenograft Model Antitumor Assays
D001549:Benzamides; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; C115711:PD 173074; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D000068877:Imatinib Mesylate; C496371:FGFR4 protein, human; C496372:Fgfr4 protein, mouse; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051499:Receptor, Fibroblast Growth Factor, Type 4