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.