EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function

Phuchareon Janyaporn; McCormick Frank; Eisele David W.Tetsu Osamu

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function

【24h】

EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function

机译：EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function

获取原文

获取原文并翻译 | 示例

掌桥外文数据库（机构版） >>

开具论文收录证明 >>

文献代查 >>

页面导航

摘要
著录项
相关主题

摘要

Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. About 14 of NSCLCs harbor mutations in epidermal growth factor receptor (EGFR). Despite remarkable progress in treatment with tyrosine kinase inhibitors (TKIs), only 5 of patients achieve tumor reduction >90. The limited primary responses are attributed partly to drug resistance inherent in the tumor cells before therapy begins. Recent reports showed that activation of receptor tyrosine kinases (RTKs) is an important determinant of this innate drug resistance. In contrast, we demonstrate that EGFR inhibition promotes innate drug resistance despite blockade of RTK activity in NSCLC cells. EGFR TKIs decrease both the mitogen-activated protein kinase (MAPK) and Akt protein kinase pathways for a short time, after which the Ras/MAPK pathway becomes reactivated. Akt inhibition selectively blocks the transcriptional activation of Ets-1, which inhibits its target gene, dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated. Furthermore, elevated c-Src stimulates Ras GTP-loading and activates Raf and MEK kinases. These observations suggest that not only ERK1/2 but also Akt activity is essential to maintain Ets-1 in an active state. Therefore, despite high levels of ERK1/2, Ets-1 target genes including DUSP6 and cyclins D1, D3, and E2 remain suppressed by Akt inhibition. Reduction of DUSP6 in combination with elevated c-Src renews activation of the Ras/MAPK pathway, which enhances cell survival by accelerating Bim protein turnover. Thus, EGFR TKIs evoke innate drug resistance by preventing Akt activity and inactivating Ets-1 function in NSCLC cells.

著录项

来源
《Proceedings of the National Academy of Sciences of the United States of America》 |2015年第29期|E3855-E3863|共9页
作者
Phuchareon Janyaporn; McCormick Frank; Eisele David W.Tetsu Osamu;
展开▼
作者单位

Univ Calif San Francisco, Sch Med, Dept Otolaryngol Head & Neck Surg, Head & Neck Canc Res Lab, San Francisco, CA 94115 USA;

Univ Calif San Francisco, Sch Med, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA;

展开▼
收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
nonsmall cell lung cancer; EGFR inhibition; tyrosine kinase inhibitors; ERK1/2 paradoxical activation; innate drug resistance;

EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function

摘要

著录项

相关主题

期刊订阅