Context: Targeting MEK in the MAPK pathway is a potentially effective therapeutic strategy for thyroid cancer.

Objective: To investigate genotype-dependent therapeutic potential of the MEK inhibitor CI-1040 for thyroid cancer.

Experimental Design: We examined the effects of CI-1040 on proliferation, apoptosis, transformation, thyroid gene re-expression, and xenograft tumor growth with respect to genotypes in 10 thyroid tumor cell lines.

Results: Cell proliferation were potently inhibited by CI-1040 in cells harboring BRAF or RAS mutations but not in cells harboring RET/PTC rearrangement or wild-type alleles. For example, the IC₅₀ values for BRAF mutation-harboring KAT10 cells and DRO cells and H-RAS mutation-harboring C643 cells were 0.365 µM, 0.031 µM and 0.429 µM, respectively, whereas the IC₅₀ values for RET/PTC1-harboring TPC1 cells and the wild-type MRO and WRO cells were 44 µM, 46 µM and 278 µM, respectively. Pro-apoptotic effect of CI-1040 was seen in DRO cells and cytostatic effect was seen in other cells. Down-regulation of cyclin D1 and re-expression of some thyroid genes were induced by CI-1040 in some BRAF mutation-harboring cells and transformation was inhibited in all cells. CI-1040 also inhibited the growth of xenograft tumors in nude mice derived from KAT10 or C643 cells but not that derived from MRO cells.

Conclusions: We for the first time demonstrated potent inhibitory effects of a MEK inhibitor, CI-1040, on thyroid cancer cells, some of which, particularly cell proliferation and tumor growth, seemed to be BRAF mutation- or RAS mutation-selective. Our data encourage a clinical trial on CI-1040 in thyroid cancer patients.