Potent Inhibition of Thyroid Cancer Cells by the MEK Inhibitor PD0325901 and Its Potentiation by Suppression of the PI3K and NF-κB Pathways

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Abstract
Background: We recently demonstrated inhibition of thyroid cancer cells by the MEK inhibitor CI-1040. The objective of this study was to use a potent new-generation MEK inhibitor PD0325901 to further investigate the therapeutic potential of specifically targeting MEK in the MAP kinase pathway for thyroid cancer. Methods: We examined the effects of PD0325901 on a variety of cellular and molecular activities of thyroid cancer cell lines with distinct genotypes. Results: PD0325901 remarkably inhibited MAP kinase pathway signaling in the thyroid cancer cells tested. It potently inhibited cell proliferation (IC50 = 0.059–0.783 μM) and arrested cell cycle at the G0/G1 phase of cells harboring BRAF or RAS mutations but not cells harboring wild-type alleles or the RET/PTC1 rearrangement. Synergistic inhibitory effects were observed when PD0325901 was combined with phosphatidylinositol 3-kinase (PI3K) or NF-κB pathway inhibitors in most cells, including the RET/PTC1-harboring cells. PD0325901 could inhibit invasion and anchorage-independent growth of thyroid cancer cells independently of the type of genetic alterations. This compound did not seem to have significant proapoptotic effects, however. Conclusions: The MEK inhibitor PD0325901 has a wide range of potent inhibitory effects on thyroid cancer cells, some of which seemed to be genotype-selective, consistent with the results previously observed with an early-generation MEK inhibitor, CI-1040. The data provide further evidence that targeted inhibition of MEK may be therapeutically effective for thyroid cancer, particularly if the PI3K and NF-κB pathways are concurrently inhibited.