Abstract
Abstract Constitutive activation of the Ras, RAF, mitogen-activated protein kinase (MEK), and extracellular signal regulated kinase (ERK) pathway is a common finding in many human cancers. Activating mutations in K-Ras or B-RAF constitute over 30% of all mutations in human tumors. Therefore, identifying therapeutic strategies to downregulate this pathway could have broad therapeutic impact. It has been demonstrated that RAF inhibitors selectively inhibit B-RAFV600E tumors and not Ras mutant tumors, despite functioning as one of the key effector enzymes downstream of Ras and upstream of MEK. In this work we demonstrate that although RAF inhibitors effectively inhibit phospho-MEK and phospho-ERK levels in B-RAFV600E cells, pathway induction is observed for RAF inhibitors in B-RAF WT/K-Ras Mutant or B-RAF WT/K-Ras WT cell lines as evidenced by increases in phospho-MEK, phospho-ERK and phospho-p90RSK levels. We also show that with increasing concentrations of RAF inhibitors, the downstream pathway can be inhibited in WT B-RAF and mutant K-Ras cell lines. Stimulation of the pathway with growth factors or serum can attenuate phospho-MEK and phospho-ERK induction upon treatment with RAF inhibitors. Additionally, mechanistic studies demonstrate that RAF inhibitors can directly activate RAF kinase activity. Taken together, our data suggests that RAF inhibitors may have opposing functions as both activators and inhibitors of the MAPK pathway, depending on cellular context. These results provide new insight into the therapeutic utility of MAPK pathway inhibitors, and emphasize the importance of correlating target occupancy with pharmacodynamic markers of efficacy, and of targeting defined genetic backgrounds in cancer treatment. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B90.
Published Version
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