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

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 (IC 50 ¼ 0.059-0.783 mM) 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-kB 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 earlygeneration 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-kB pathways are concurrently inhibited.

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An update on molecular biology of thyroid cancers

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The influence of the BRAF V600E mutation in thyroid cancer cell lines on the anticancer effects of 5-aminoimidazole-4-carboxamide-ribonucleoside

“…This mutation induces constitutive activation of mitogen-activated protein kinase (MAPK) signaling, and is associated with uncontrolled cell growth, proliferation, and tumorigenesis (Gray-Schopfer et al 2005, Xing 2005, Dhomen & Marais 2007. Several studies found that mutation of BRAF was associated with cancer cell sensitivity to a BRAF/MEK blockade (Dignam et al 1983, Cohen et al 2003, Ball et al 2007, Liu et al 2007, Liu & Xing 2008, but the detailed mechanisms are not well understood. Recent reports have demonstrated that AMPK-mediated growth inhibition of melanoma cells harboring the BRAF V600E mutation involves the RAF-MEK-ERK (MAPK) pathway (Martin et al 2009, Zheng et al 2009.…”