Abstract 3723: TAS-115, a novel MET + VEGFRs dual inhibitor, decreases the cytotoxic anticancer drug resistance in lung cancer
Authors: Kunii Eiji , Ozasa Hiroaki , Oguri Tetsuya , Maeno Ken , Takakuwa Osamu , Uemura Takehiro , Akio Niimi 
Published: May 2015

c-Met is the receptor tyrosine kinase for hepatocyte growth factor (HGF). c-Met/HGF signal stimulates the expression of many downstream genes, which are associated with biological events such as oncogenesis, cancer metastasis and drug resistance. The enhanced c-Met/HGF signal is detected in various cancer cells containing lung cancer. Interestingly, recent studies revealed this is a new mechanism of acquired resistance to anticancer agents, especially epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gefitinib. TAS-115 [4-[2-fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamide] is identified as a novel potent c-Met and VEGFR dual inhibitor. In biochemical assay, it was identified to be a potent Adenosine Triphosphate (ATP) competitive inhibitor of both c-Met and VEGFR that is equal or more potent than those of other known inhibitors such as crizotinib. In this study, we investigate whether c-Met inhibition by TAS-115 influence the resistance against cytotoxic anticancer agents in several resistant cell lines harboring c-Met activation. We found that the levels of c-Met expression and activation in various drug resistances, including the 7-ethyl-10-hydroxycamptothesin (SN-38) -resistant lung cancer cell lines (PC-6/SN-38 GEM) and gemcitabine (GEM) -resistant lung cancer cell lines (PC-9/GEM) were enhanced relative to the parental cells by western blotting (WB). We confirmed that TAS-115 dose-dependently inhibits phoshorylation of c-Met and downstream signals, ERK1/2 and AKT, in PC-6/SN-38 cells and PC-9/GEM cells. MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assay was performed to determine whether certain concentrations TAS-115 inhibit cell growths of PC-6/SN-38 and PC-9/GEM cells. Cell growth of PC-6/SN-38 cells was not affected by treatment with TAS-115 (2 or 4 μM) for 72h. The same results were observed in PC-9/GEM cells that were treated with TAS-115 (4 or 8 μM). These results suggested that c-MET inhibition is not enough to inhibit cell growth when treated with TAS-115 alone. Next, we exposed PC-6/SN-38 cells to DMSO or TAS-115 (2 or 4 μM) in combination with SN-38 (12.5 nM) for 72 h. Although PC-6/SN-38 cells were resistant to SN-38, the combined treatment with TAS-115 resulted in growth inhibition in a dose-dependent manner. We got the same results in PC-9/GEM cells when combined treatment with GEM and TAS-115. These results show that inhibition of c-Met signaling decrease the resistance of cytotoxic anticancer agent resistant cells. In conclusion, TAS-115 might become to overcome the resistance against cytotoxic anticancer agents by c-Met/HGF signal.

Citation Format: Eiji Kunii, Hiroaki Ozasa, Tetsuya Oguri, Ken Maeno, Osamu Takakuwa, Takehiro Uemura, Niimi Akio. TAS-115, a novel MET + VEGFRs dual inhibitor, decreases the cytotoxic anticancer drug resistance in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3723. doi:10.1158/1538-7445.AM2014-3723