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

Background/Objective:
Pancreatic ductal adenocarcinoma (PDA) is among the deadliest cancers, largely due to limited effective treatments. P21-activated kinases (PAKs) contribute to PDA progression by promoting cell proliferation, migration, and resistance to chemotherapy. This study evaluated the combined effects of the PAK inhibitor PF-3758309 with standard chemotherapeutics (gemcitabine, 5-fluorouracil [5-FU], or abraxane) on patient-derived PDA cell lines and explored underlying mechanisms.

Methods:
PDA cell lines were treated with PF-3758309 alone or in combination with gemcitabine, 5-FU, or abraxane, and cell proliferation was assessed. Protein expression was analyzed via Western blot. For in vivo studies, PDA cells were implanted into SCID mice, which were treated with saline, PF-3758309, gemcitabine, their combination, or abraxane. Tumor volume and weight were measured.

Results:
PAK1 expression correlated with CK19, while PAK4 aligned with α-SMA and palladin. PF-3758309 combined with any of the chemotherapeutic agents significantly reduced cell growth in vitro. In vivo, PF-3758309 plus gemcitabine most effectively suppressed tumor growth by reducing proliferation. PF-3758309 also downregulated HIF-1α, palladin, and α-SMA expression in vitro and in vivo.

Conclusions:
The PAK inhibitor PF-3758309 enhances the efficacy of multiple chemotherapies against PDA. Its combination with gemcitabine demonstrates anti-tumor effects comparable to gemcitabine plus abraxane, highlighting its potential as a targeted therapeutic strategy for PDA.