Impaired SHP2-mediated extracellular signal-regulated kinase activation contributes to gefitinib sensitivity of lung cancer cells with epidermal growth factor receptor-activating mutations.
Impaired SHP2-mediated extracellular signal-regulated kinase activation contributes to gefitinib sensitivity of lung cancer cells with epidermal growth factor receptor-activating mutations.
复制标题
DOI：
10.1158/0008-5472.can-09-3421
复制
发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Lauffenburger DA
中科院分区：
文献类型：
--
作者：
Lazzara MJ;Lane K;Chan R;Jasper PJ;Yaffe MB;Sorger PK;Jacks T;Neel BG;Lauffenburger DA
大多数非小细胞肺癌（NSCLC）显示表皮生长因子受体（EGFR）表达升高，但对EGFR激酶抑制剂的反应主要限于携带EGFR激活突变的NSCLC。这些突变与包括PI 3 K/AKT和STAT 3/5在内的生存途径的活性增加有关。我们报告说，EGFR激活突变也令人惊讶地导致降低的能力，激活ERK相比，野生型EGFR。在表达突变型EGFR的NSCLC细胞和小鼠胚胎成纤维细胞中，这种对ERK的影响与EGFR内化减少和SHP 2磷酸化减少相关，SHP 2是ERK完全激活所需的酪氨酸磷酸酶。我们进一步证明ERK激活水平影响细胞对吉非替尼的反应。当ERK激活通过MEK的组成型活性突变体的表达而增强时，EGFR突变的NSCLC细胞显示出降低的吉非替尼敏感性。相反，在表达野生型EGFR的NSCLC细胞系中，与吉非替尼单独治疗相比，吉非替尼治疗沿着MEK抑制或在MEK抑制后增加死亡应答。我们的研究结果表明，EGFR激活突变可能会促进一些生存途径，但同时损害其他人。这种控制细胞对吉非替尼反应的网络的多变量改变，我们称之为“癌基因失衡”，预示着治疗吉非替尼耐药NSCLC的潜在更广泛的能力。
Most non-small cell lung cancers (NSCLC) display elevated expression of epidermal growth factor receptor (EGFR), but response to EGFR kinase inhibitors is predominantly limited to NSCLC harboring EGFR-activating mutations. These mutations are associated with increased activity of survival pathways including PI3K/AKT and STAT3/5. We report that EGFR-activating mutations also surprisingly lead to decreased ability to activate ERK compared to wild-type EGFR. In NSCLC cells and mouse embryonic fibroblasts expressing mutant EGFR, this effect on ERK correlates with decreased EGFR internalization and reduced phosphorylation of SHP2, a tyrosine phosphatase required for the full activation of ERK. We further demonstrate that ERK activation levels impact cellular response to gefitinib. NSCLC cells with EGFR mutation display reduced gefitinib sensitivity when ERK activation is augmented by expression of constitutively active mutants of MEK. Conversely, in an NSCLC cell line expressing wild-type EGFR, gefitinib treatment along with or following MEK inhibition increases death response compared to treatment with gefitinib alone. Our results demonstrate that EGFR-activating mutations may promote some survival pathways but simultaneously impair others. This multivariate alteration of the network governing cellular response to gefitinib, which we term “oncogene imbalance”, portends a potentially broader ability to treat gefitinib-resistant NSCLC.