SU1498 is a direct inhibitor of ERK and sensitizes breast cancer cells to stress‐induced apoptosis

SU1498, an inhibitor of vascular endothelial growth factor receptor‐2 (VEGFR‐2) has been used to study receptor function. In addition to its anti‐VEGFR‐2 activity, SU1498 was found to stimulate the accumulation of phosphorylated extracellular signal‐regulated protein kinases (ERKs), generally an indication of ERK activation, in human umbilical vein endothelial cells. The enhanced accumulation of phospho‐ERKs is observed only in stimulated cells, SU1498 by itself is ineffective. Activation of the classical MAP kinase signalling pathway was required to generate phospho‐ERK. However, SU1498 also blocked the kinase activity of phospho‐ERK, both in a direct assay and in cells treated with the compound. Therefore, there was an apparent contradiction, an ERK inhibitor that results in the hyperphosphorylation of ERK. SU1498 prevents dephosphorylation of phospho‐ERK by MAP kinase phosphatase‐1, without directly affecting the phosphatase activity, suggesting that SU1498 associates with phospho‐ERK, inhibiting kinase activity, but also making the kinase inaccessible to ERK‐specific phosphatases. In breast cancer cells, SU1498 inhibits proliferation and sensitizes the cells to stress‐induced apoptosis. As resistance to apoptosis and enhanced proliferation are both characteristics of cancer cells, these studies suggest a novel way in which MAP kinase signaling pathway may be blocked in human cancers. Supported by a NSERC grant to ATK