Co-inhibition of SMAD and MAPK signaling enhances 124I uptake in BRAF-mutant thyroid cancers.

Autor:	Luckett KA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Cracchiolo JR; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Krishnamoorthy GP; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Leandro-Garcia LJ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Nagarajah J; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Saqcena M; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Lester R; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Im SY; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Zhao Z; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Lowe SW; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA., de Stanchina E; Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Sherman EJ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Weill-Cornell Medical College, New York, New York, USA., Ho AL; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Weill-Cornell Medical College, New York, New York, USA., Leach SD; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Knauf JA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Fagin JA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Weill-Cornell Medical College, New York, New York, USA.
Jazyk:	angličtina
Zdroj:	Endocrine-related cancer [Endocr Relat Cancer] 2021 May 18; Vol. 28 (6), pp. 391-402. Date of Electronic Publication: 2021 May 18.
DOI:	10.1530/ERC-21-0017
Abstrakt:	Constitutive MAPK activation silences genes required for iodide uptake and thyroid hormone biosynthesis in thyroid follicular cells. Accordingly, most BRAFV600E papillary thyroid cancers (PTC) are refractory to radioiodide (RAI) therapy. MAPK pathway inhibitors rescue thyroid-differentiated properties and RAI responsiveness in mice and patient subsets with BRAFV600E-mutant PTC. TGFB1 also impairs thyroid differentiation and has been proposed to mediate the effects of mutant BRAF. We generated a mouse model of BRAFV600E-PTC with thyroid-specific knockout of the Tgfbr1 gene to investigate the role of TGFB1 on thyroid-differentiated gene expression and RAI uptake in vivo. Despite appropriate loss of Tgfbr1, pSMAD levels remained high, indicating that ligands other than TGFB1 were engaging in this pathway. The activin ligand subunits Inhba and Inhbb were found to be overexpressed in BRAFV600E-mutant thyroid cancers. Treatment with follistatin, a potent inhibitor of activin, or vactosertib, which inhibits both TGFBR1 and the activin type I receptor ALK4, induced a profound inhibition of pSMAD in BRAFV600E-PTCs. Blocking SMAD signaling alone was insufficient to enhance iodide uptake in the setting of constitutive MAPK activation. However, combination treatment with either follistatin or vactosertib and the MEK inhibitor CKI increased 124I uptake compared to CKI alone. In summary, activin family ligands converge to induce pSMAD in Braf-mutant PTCs. Dedifferentiation of BRAFV600E-PTCs cannot be ascribed primarily to activation of SMAD. However, targeting TGFβ/activin-induced pSMAD augmented MAPK inhibitor effects on iodine incorporation into BRAF tumor cells, indicating that these two pathways exert interdependent effects on the differentiation state of thyroid cancer cells.
Databáze:	MEDLINE
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