Activation of the RAS/RAF/ERK Signaling Pathway Contributes to Resistance to Sunitinib in Thyroid

Context: Sunitinib is currently being evaluated in advanced human thyroid carcinomas, based on the rationale that the vascular endothelial growth factor and platelet-derived growth factor re-ceptors and the RET/PTC rearrangement are valuable targets for the treatment of thismalignancy. However, criteria for selecting thyroid tumors that may benefit from sunitinib are lacking. Design: The effect of activating somatic mutations in the KRAS and BRAF genes on the respon-siveness to sunitinibwas evaluated in a panel of thyroid cancer cell lines harboringwild-typeKRAS and BRAF genes, the RET/PTC1 rearrangement, the G12R KRAS, or the V600E BRAF mutation. Results: Sunitinibwas found to selectively inhibit cell proliferation, induce cell accumulation in the G0-G1 phase, and inhibit the phosphorylation of ERK1/2 in both KRAS/BRAF wild-type thyroid cancer cells and in tumor cells harboring the RET/PTC rearrangement, whereas it was completely ineffective in KRAS- or BRAF-mutated thyroid carcinoma cells. This differential antitumor activity of sunitinib did not correlate with the expression profile of the vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor- and cKIT genes. Of note, the constitutive activation of RAS/RAF/ERK signaling in KRAS/BRAF wild-type cells by transfection of the R12 HRAS or V600E BRAF mutants or stimulation with epithelial growth factor resulted in th