Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer.
Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer.
复制标题
DOI：
10.1158/0008-5472.226.65.1
复制
发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
J. Amann;Shailaja Kalyankrishna;P. Massion;J. Ohm;L. Girard;H. Shigematsu;M. Peyton;Denise M. Juroske-Denise-M.
中科院分区：
文献类型：
--
作者：
J. Amann;Shailaja Kalyankrishna;P. Massion;J. Ohm;L. Girard;H. Shigematsu;M. Peyton;Denise M. Juroske-Denise-M.
表皮生长因子受体（EGFR）偶尔在非小细胞肺癌（NSCLC）中扩增和/或突变，并可与HER受体家族的其他成员共表达，形成功能性异源二聚体。因此，我们研究了肺癌细胞系EGFR基因拷贝数的改变，EGFR和其他HER家族成员的表达增强，EGFR编码序列突变，并将这些发现与EGFR抑制剂治疗反应和配体诱导信号传导动力学相关。我们在这里显示，EGFR酪氨酸激酶结构域的体细胞缺失与NSCLC中EGFR基因拷贝数增加相关。用特异性EGFR酪氨酸激酶抑制剂（TKI）吉非替尼或厄洛替尼或EGFR抑制性抗体西妥昔单抗治疗可诱导HCC 827细胞凋亡，HCC 827是一种EGFR基因扩增和外显子19缺失的NSCLC细胞系。H1819是一种表达高水平EGFR、ErbB 2和ErbB 3但具有野生型EGFR的NSCLC细胞系，对TKI表现出中等敏感性。在两种细胞系中，配体诱导的受体酪氨酸磷酸化延迟和延长，AKT组成性磷酸化（但仍可被EGFR TKI激活）。因此，除了EGFR突变，NSCLC细胞中的其他因素，如ErbB家族成员的高表达，可能组成性激活AKT并使细胞对EGFR抑制剂敏感。
Epidermal growth factor receptor (EGFR) is occasionally amplified and/or mutated in non-small cell lung cancer (NSCLC) and can be coexpressed with other members of the HER receptor family to form functional heterodimers. We therefore investigated lung cancer cell lines for alterations in EGFR gene copy number, enhanced expression of EGFR and other HER family members, and EGFR coding sequence mutations and correlated these findings with response to treatment with the EGFR inhibitors and the kinetics of ligand-induced signaling. We show here that somatic deletions in the tyrosine kinase domain of EGFR were associated with increased EGFR gene copy number in NSCLC. Treatment with the specific EGFR tyrosine kinase inhibitors (TKI) gefitinib or erlotinib or the EGFR inhibitory antibody cetuximab induced apoptosis of HCC827, a NSCLC cell line with EGFR gene amplification and an exon 19 deletion. H1819, a NSCLC cell line that expresses high levels of EGFR, ErbB2, and ErbB3 but has wild-type EGFR, showed intermediate sensitivity to TKIs. In both cell lines, ligand-induced receptor tyrosine phosphorylation was delayed and prolonged and AKT was constitutively phosphorylated (but remained inhibitable by EGFR TKI). Thus, in addition to EGFR mutations, other factors in NSCLC cells, such as high expression of ErbB family members, may constitutively activate AKT and sensitize cells to EGFR inhibitors.