title: Tyrosine kinase receptors as molecular targets in pheochromocytomas and paragangliomas.
abstract: Pheochromocytomas and paragangliomas are neuroendocrine tumors shown to be responsive to multitargeted tyrosine kinase inhibitor (TKI) treatment. Despite growing knowledge regarding their genetic basis, the ability to predict behavior in these tumors remains challenging. There is also limited knowledge of their tyrosine kinase receptor expression and whether the clinical response observed to the TKI sunitinib relates only to its anti-angiogenic properties or also due to a direct effect on tumor cells. To answer these questions, an in vitro model of sunitinib treatment of a pheochromocytoma cell line was created. Sunitinib targets (VEGFRs, PDGFRs, and C-KIT), FGFRs, and cell cycle regulatory proteins were investigated in human tissue microarrays. SDHB immunohistochemistry was used as a surrogate marker for the presence of succinate dehydrogenase mutations. The FGFR4 G388R single nucleotide polymorphism was also investigated. Sunitinib treatment in vitro decreases cell proliferation mainly by targeting cell cycle, DNA metabolism, and cell organization genes. FGFR1, -2, and -4, VEGFR2, PDGFRα, and p16 were overexpressed in primary human pheochromocytomas and paragangliomas. Discordant results were observed for VEGFR1, p27, and p21 overexpressed in paragangliomas but underexpressed in pheochromocytomas; PDGFRβ, Rb, and Cyclin D1 overexpressed in paragangliomas only; and FGFR3 overexpressed in pheochromocytomas and underexpressed in paragangliomas. Low expression of C-KIT, p53, and Aurora kinase A and B was observed. Nuclear FGFR2 expression was associated with increased risk of metastasis (odds ratio (OR)=7.61, P=0.008), as was membranous PDGFRα (OR=13.71, P=0.015), membranous VEGFR1 (OR=8.01, P=0.037), nuclear MIB1 (OR=1.26, P=0.008), and cytoplasmic p27 (OR=1.037, P=0.030). FGFR3, VEGFR2, and C-KIT levels were associated with decreased risk of metastasis. We provide new insights into the mechanistic actions of sunitinib in pheochromocytomas and paragangliomas, and support current evidence that multitargeted TKIs might be a suitable treatment alternative for these tumors.
authors.affiliation: Department of Pathology, University Health Network, Toronto, ON, Canada.
authors.forename: Clarissa A
authors.initials: CA
authors.lastname: Cassol
authors.affiliation: Department of Pathology, University Health Network, Toronto, ON, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Winer
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Miao
authors.initials: M
authors.lastname: Guo
authors.affiliation: 1] Ontario Cancer Institute, University Health Network, Toronto, ON, Canada [2] Department of Medicine, University Health Network, Toronto, ON, Canada.
authors.forename: Shereen
authors.initials: S
authors.lastname: Ezzat
authors.affiliation: 1] Department of Pathology, University Health Network, Toronto, ON, Canada [2] Ontario Cancer Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D010235:Paraganglioma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010673:Pheochromocytoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000077210:Sunitinib; D046888:Tissue Array Analysis
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013385:Succinate Dehydrogenase; C496371:FGFR4 protein, human; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib