title: Influence of RET mutations on the expression of tyrosine kinases in medullary thyroid carcinoma.
abstract: The therapeutic options for patients with metastatic medullary thyroid carcinoma (MTC) have recently increased due to the development of tyrosine kinase inhibitors (TKIs), some of which have achieved remarkable clinical responses in MTC patients. However, the molecular basis for the large variability in TKI responses is unknown. In this exploratory study, we investigated the expression of eight key TKI target proteins (EGFR, KIT, MET, PDGFRB, VEGF (VEGFA), VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4)) by immunohistochemistry in 103 molecularly characterized MTC samples and identified the associated clinical and molecular features. A number of MTC samples exhibited a high expression of VEGFR2 and VEGFR3, which were overexpressed in 57 and 43% of the MTC samples respectively. VEGFR1, PDGFRB, VEGF, KIT, and MET were present in 34-20% of the cases, while EGFR was highly expressed in only 10% of the MTC samples. Some proteins exhibited large differences in expression between sporadic and familial cases, suggesting that different RET mutations may be associated with the immunohistochemical profiles. MTC samples with the C634 RET mutation exhibited a higher expression of VEGFR3 and KIT than the M918T RET-mutated and non-mutated RET tumor samples (P=0.005 and P=0.007 respectively) and a lower expression of VEGFR1 (P=0.04). Non-mutated RET MTC cases exhibited a lower expression of PDGFRB (P=0.04). Overall, this is the first study, to our knowledge, to show that multiple TKI targets are highly expressed in a subset of MTCs, suggesting that molecular stratification of patients may have the potential to improve TKI therapies for MTC.
authors.affiliation: Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO), Melchor Fernández Almagro 3, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.forename: Iván
authors.initials: I
authors.lastname: Muñoz-Repeto
authors.forename: Lucia
authors.initials: L
authors.lastname: Inglada-Pérez
authors.forename: Aguirre A
authors.initials: AA
authors.lastname: de Cubas
authors.forename: Veronika
authors.initials: V
authors.lastname: Mancikova
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Maliszewska
authors.forename: Alvaro
authors.initials: A
authors.lastname: Gómez
authors.forename: Rocío
authors.initials: R
authors.lastname: Letón
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Leandro-García
authors.forename: Iñaki
authors.initials: I
authors.lastname: Comino-Méndez
authors.forename: Lara
authors.initials: L
authors.lastname: Sanchez
authors.forename: Cristina
authors.initials: C
authors.lastname: Alvarez-Escolá
authors.forename: Javier
authors.initials: J
authors.lastname: Aller
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascón
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018278:Carcinoma, Neuroendocrine; D002648:Child; D066246:ErbB Receptors / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055815:Young Adult
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D019859:Proto-Oncogene Proteins c-met; D051096:Proto-Oncogene Proteins c-ret; D020797:Receptor, Platelet-Derived Growth Factor beta; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: EGFR; KIT; MET; PDGFRB; RET mutation; VEGF; VEGFR1; VEGFR2; VEGFR3; medullary thyroid carcinoma; tyrosine kinase inhibitors