Lev D C, Kim L S, Melnikova V, Ruiz M, Ananthaswamy H N, Price J E
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Br J Cancer. 2004 Aug 16;91(4):795-802. doi: 10.1038/sj.bjc.6602051.
One of the major targets for breast cancer therapy is the epidermal growth factor receptor (EGFR) and related receptors, which signal via different signal transduction pathways including the mitogen-activated protein kinase (MAPK) pathway. This study determined whether there is a correlation between EGFR/HER2 status and MAPK (ERK1/2) phosphorylation in breast cancer cells, and how this affects the response to an inhibitor of the receptors. Expression of EGFR, HER2 and phosphorylated ERK1/2 were measured by immunoblotting in a panel of breast cancer cell lines. Several lines expressed high levels of pERK1/2, with no obvious correlation with the level of EGFR/HER2. The EGFR tyrosine kinase inhibitor PKI166 inhibited growth and induced apoptosis in some cells with high levels of growth factor receptors (MDA-MB-468, SUM149, SKBR3), but was less effective in cells that also had high basal ERK1/2 activity (MDA-MB-231). The combination of an inhibitor of MAPK signalling (U0126) and PKI166 produced significantly more inhibition and apoptosis than either agent alone. This suggests that constitutive activation of the MAPK pathway may bypass inhibition of EGFR/HER2 tyrosine kinases, and lead to insensitivity to agents targeting the receptors. However, inhibiting both EGFR/HER2 and MAPK signalling can result in significant growth inhibition and apoptosis of EGFR-expressing breast cancer cells.
乳腺癌治疗的主要靶点之一是表皮生长因子受体（EGFR）及相关受体，它们通过包括丝裂原活化蛋白激酶（MAPK）途径在内的不同信号转导途径进行信号传导。本研究确定了乳腺癌细胞中EGFR/HER2状态与MAPK（ERK1/2）磷酸化之间是否存在相关性，以及这如何影响对受体抑制剂的反应。通过免疫印迹法在一组乳腺癌细胞系中检测EGFR、HER2和磷酸化ERK1/2的表达。几条细胞系表达高水平的pERK1/2，与EGFR/HER2水平无明显相关性。EGFR酪氨酸激酶抑制剂PKI166在一些具有高水平生长因子受体的细胞（MDA-MB-468、SUM149、SKBR3）中抑制生长并诱导凋亡，但在也具有高基础ERK1/2活性的细胞（MDA-MB-231）中效果较差。MAPK信号传导抑制剂（U0126）和PKI166联合使用比单独使用任何一种药物产生的抑制和凋亡作用都显著更强。这表明MAPK途径的组成性激活可能绕过对EGFR/HER2酪氨酸激酶的抑制，并导致对靶向这些受体的药物不敏感。然而，抑制EGFR/HER2和MAPK信号传导均可导致表达EGFR的乳腺癌细胞显著生长抑制和凋亡。
