The Novel, Orally Bioavailable CDK9 Inhibitor Atuveciclib Sensitises Pancreatic Cancer Cells to TRAIL-induced Cell Death

Abstract

Background/aim: This study was designed to analyse the effects of the novel, orally bioavailable CDK9-inhibitor Atuveciclib (BAY 1143572) in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) on pancreatic ductal adenocarcinoma (PDAC) cancer cells.

Materials and methods: To assess the effect of combinatorial use of atuveciclib and TRAIL on pancreatic cancer cells, we used an MTT assay, colony formation assay, flow cytometry, and western blot analysis.

Results: Atuveciclib combined with TRAIL significantly reduced the viability of pancreatic cancer cells and their colony formation potential by inducing apoptosis and cell-cycle arrest. Atuveciclib sensitised PDAC cells to TRAIL-induced cell death through the concomitant suppression of cFlip and Mcl-1. A gemcitabine-resistant PDAC cell-line and patient-derived xenograft (PDX) cell lines were also suppressed by this combinatorial approach.

Conclusion: This study provides the basis for further preclinical and clinical evaluation of combined treatment with atuveciclib and TRAIL.

Keywords: Atuveciclib; CDK9; TRAIL; apoptosis; pancreatic cancer; pancreatic ductal adenocarcinoma.