Potent inhibition of thyroid cancer cells by the MEK inhibitor PD0325901 and its potentiation by suppression of the PI3K and NF-kappaB pathways.
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) = 0.059-0.783 microM) 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-kappaB 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-kappaB pathways are concurrently inhibited.
Liu
Dingxie
D
Division of Endocrinology and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, 1830 E. Monument Street, Baltimore, MD 21287, USA.
Xing
Mingzhao
M
D001549:Benzamides / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004357:Drug Synergism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
D001549:Benzamides; D002867:Chromones; D006575:Heterocyclic Compounds, 3-Ring; D009025:Morpholines; D016328:NF-kappa B; C456319:PS1145; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C506614:mirdametinib; D004159:Diphenylamine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; D018631:ras Proteins