期刊
ONCOTARGET
卷 9, 期 2, 页码 1641-1655出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.22895
关键词
Golgi apparatus; ADP ribosylation factor 1 (Arf1); non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR); acquired resistance
资金
- Adaptable & Seamless Technology Transfer Program through Target-driven R&D (A-STEP) from the Japan Agency for Medical Research and Development (AMED) [AS2614144Q]
- Vehicle Racing Commemorative Foundation
- JSPS KAKENHI [17K07230]
- Grants-in-Aid for Scientific Research [17H06324, 17K07230, 16H05105] Funding Source: KAKEN
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) were demonstrated to provide survival benefit in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR; however, emergence of acquired resistance to EGFR-TKIs has been shown to cause poor outcome. To overcome the TKI resistance, drugs with different mode of action are required. We previously reported that M-COPA (2-methylcoprophilinamide), a Golgi disruptor, suppressed the growth of gastric cancers overexpressing receptor tyrosine kinases (RTKs) such as hepatocyte growth factor receptor (MET) via downregulating their cell surface expression. In this study, we examined the antitumor effect of M-COPA on NSCLC cells with TKI resistance. As a result, M-COPA effectively downregulated cell surface EGFR and its downstream signals, and finally exerted in vivo antitumor effect in NSCLC cells harboring secondary (T790M/del19) and tertiary (C797S/T790M/del19) mutated EGFR, which exhibit acquired resistance to first-and third generation EGFR-TKIs, respectively. M-COPA also downregulated MET expression potentially involved in the acquired resistance to EGFR-TKIs via bypassing the EGFR pathway blockade. These results provide the first evidence that targeting the Golgi apparatus might be a promising therapeutic strategy to overcome the vicious cycle of TKI resistance in EGFR-mutated NSCLC cells via downregulating cell surface RTK expression.
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