Targeting the Golgi apparatus to overcome acquired resistance of non-small cell lung cancer cells to EGFR tyrosine kinase inhibitors

• Published in: Oncotarget Vol. 9; no. 2; pp. 1641 - 1655
• Main Authors: Ohashi, Yoshimi, Okamura, Mutsumi, Katayama, Ryohei, Fang, Siyang, Tsutsui, Saki, Akatsuka, Akinobu, Shan, Mingde, Choi, Hyeong-Wook, Fujita, Naoya, Yoshimatsu, Kentaro, Shiina, Isamu, Yamori, Takao, Dan, Shingo
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 05.01.2018
• Subjects: Research Paper; epidermal growth factor receptor (EGFR); ADP ribosylation factor 1 (Arf1); acquired resistance; non-small cell lung cancer (NSCLC); Golgi apparatus
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.22895

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) 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 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 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 downregulating cell surface RTK expression.