Anti-tumor effect of NVP-BKM120 alone or in combination with MEK162 contra biliary tract cancer.

Abstract

Phosphoinositide-3-kinase (PI3K)/AKT/mTOR signaling is one of the most significant pathways regulating tremendous cell processes such as cell proliferation, cell cycle and cell metabolism in many types of cancer. Given that PI3 kinase is the outset of the whole signaling, an agent potently targeting PI3K, such as NVP-BKM120 was expected to bring phenomenal outcome in regulation of cell processes stated previously. In our study, the investigation of NVP-BKM120 against biliary tract cancer was conducted under the hypothesis of that biliary tract cancer cell lines would display different sensitiveness according to the different mutation status of PIK3CA and K-RAS. Considering high frequency of the reports indicating that PI3K pathway inhibition may induce the activation of RAS/RAF/MEK axis, we also conducted the combination study of BKM120 along with MEK162, a MEK inhibitor. In our study, BKM120 inhibited cell proliferation of biliary tract cancer cells in the short term and also successfully stagnated anchorage-independent cell growth in the long term except the cell line with the co-mutation of PIK3CA and K-RAS (SNU-869). BKM120 successfully blockaded key molecules of PI3K pathway such as P-AKT, P-p70s6k and P-4E-BP1 in two wild-type cell lines (SNU-245 and SNU-1196). In K-RAS mutant cell line (HuCCT-1), BKM120 failed to block PI3K pathway signals, though it conduced to G2 arrest in this cell line in cell cycle analysis. In co-mutant PIK3CA/K-RAS cell line (SNU-869), BKM120 failed to induce cell cycle arrestment and in western blot assay it also failed to block PI3K pathway signals by inducing a restoration of P-4ebp1 at 48h. In migration assay, BKM120 could inhibit cell migration both in wild type and K-RAS mutant cell lines but not in the cell line carrying co-mutations. In combination study with MEK162, cell proliferation was inhibited synergistically in the selected cell lines except K-RAS mutant cell line (HuCCT-1). Taken together, BKM120 has a potent anti-tumor effect in wild-type biliary tract cancer cells. Combination study of BKM120 with MEK162 showed an enhanced anti-tumor effect in the selected cell lines especially in one with co-mutation of PIK3CA and K-RAS, but not in K-RAS mutant cell. Our study strongly suggests that BKM120 can be a promising therapeutic agent alone or in combination in the treatment of biliary tract cancer.