PAK inhibition by PF-3758309 enhanced the sensitivity of multiple chemotherapeutic reagents in patient-derived pancreatic cancer cell lines.

Abstract

Pancreatic ductal adenocarcinoma (PDA) remains the most lethal malignancy due to lack of an effective treatment. P21-activated kinases (PAKs) play a key role not only in cell proliferation and migration, but also in mediating chemo-resistance in PDA. The aim of this study was to investigate the combined effect of a PAK inhibitor PF-3758309 with multiple chemotherapeutic reagents on a panel of patient-derived PDA cell lines, and potential mechanisms involved. Cells were treated with PF-3758309 plus or minus gemcitabine, 5-fluorouracil (5-FU) or abraxane, and cell growth was determined using a cell proliferation assay kit. Protein expression profiles were measured by Western blot. PDA cells were subcutaneously injected into the flanks of SCID mice which were then treated with saline, gemcitabine, PF-3758309, gemcitabine plus PF-3758309 or abraxane. Tumour growth was measured by volume and weight. PAK1 was correlated with CK19 expression, and PAK4 with α-SMA and palladin expression. Combination of PF-3758309 with 5-FU, gemcitabine or abraxane further suppressed cell growth of patient-derived PDA cell lines in vitro. The combination of PF-3758309 with gemcitabine maximally inhibited tumour growth in vivo by suppressing cell proliferation. PF-3758309 inhibited the expression of HIF-1α, palladin and α-SMA both in vitro and in vivo. PAK inhibitor PF-3758309 can enhance anti-tumour effects of multiple chemotherapeutic reagents on a panel of patient-derived PDA cell lines. Combination of PF-3758309 with gemcitabine achieves comparable efficacy to combination of gemcitabine with abraxane, and thus provides a potential targeted therapy in the management of PDA.