L1000CDS2 약물 유전체 분석을 통한 췌장암 신약 후보 BX-795의 발굴

Abstract

Pancreatic cancer is one of the most lethal cancers worldwide, because there is no diagnostic tool and no effective therapeutic agents. Therefore, novel therapeutic strategies are desperately needed. In this study, the expression profiles of 10 pancreatic cancer datasets were collected from GEO, and GEO2R tool was used to obtain gene expression changes in normal and tumor tissue sample. Then, using L1000CDS2, which predicts a substance that can drive or reverse such gene expression changes, we found drugs that reverse PDAC gene expression changes and selected six out of 20 initial candidates. We measured IC50 for the six drugs and identified BX-795, a PDK1/TBK1 inhibitor, as a promising candidate. Effect of BX-795 was evaluated by proliferation assay, western blotting and trasnwell assay. We found BX-795 efficiently inhibits proliferation in PDC 110621 but not in 115026, showing approximately 60 times higher IC50 value. BX-795, the mTOR/GSK3β pathway was inhibited and subsequent apoptosis was induced. In addition, BX-795 changed the cell shape and inhibited migration, confirmed through the transwell assay. As p-ERK was increased by BX-795, we also examined the combinatory effect of BX-795 with a MEK inhibitor. As a result, we found an additive cytotoxic effect of BX-795 and MEK inhibitor trametinib. Finally, we showed BX-795 is as effective as Gemcitabine to reduce tumor growth in patient-derived xenograft models. Collectively, these results demonstrate BX-795 as a novel therapeutic candidate for pancreatic cancer treatment.