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|Ref Type||Journal Article|
|Authors||Ohashi Y, Okamura M, Hirosawa A, Tamaki N, Akatsuka A, Wu KM, Choi HW, Yoshimatsu K, Shiina I, Yamori T, Dan S|
|Title||M-COPA, a Golgi Disruptor, Inhibits Cell Surface Expression of MET Protein and Exhibits Antitumor Activity against MET-Addicted Gastric Cancers.|
|Date||2016 Jul 01|
|Abstract Text||The Golgi apparatus is responsible for transporting, processing, and sorting numerous proteins in the cell, including cell surface-expressed receptor tyrosine kinases (RTK). The small-molecule compound M-COPA [2-methylcoprophilinamide (AMF-26)] disrupts the Golgi apparatus by inhibiting the activation of Arf1, resulting in suppression of tumor growth. Here, we report an evaluation of M-COPA activity against RTK-addicted cancers, focusing specifically on human gastric cancer (GC) cells with or without MET amplification. As expected, the MET-addicted cell line MKN45 exhibited a better response to M-COPA than cell lines without MET amplification. Upon M-COPA treatment, cell surface expression of MET was downregulated with a concurrent accumulation of its precursor form. M-COPA also reduced levels of the phosphorylated form of MET along with the downstream signaling molecules Akt and S6. Similar results were obtained in additional GC cell lines with amplification of MET or the FGF receptor FGFR2 MKN45 murine xenograft experiments demonstrated the antitumor activity of M-COPA in vivo Taken together, our results offer an initial preclinical proof of concept for the use of M-COPA as a candidate treatment option for MET-addicted GC, with broader implications for targeting the Golgi apparatus as a novel cancer therapeutic approach. Cancer Res; 76(13); 3895-903. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|M-COPA||AMF-26||M-COPA is a small-molecule that inhibits Arf1 activation, which interferes with function of the Golgi apparatus and leads to decreased tumor growth (PMID: 27197184, PMID: 31484543).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FGFR2 amp||gastric signet ring cell adenocarcinoma||sensitive||M-COPA||Preclinical - Cell culture||Actionable||In a preclinical study, treatment with M-COPA resulted in decreased Fgfr2 cell surface expression and phosphorylation and reduced growth of an FGFR2-amplified signet cell gastric cancer cell line in culture (PMID: 27197184).||27197184|