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

  • Anticancer Res. 2021 Dec;41(12):5973-5985. doi: 10.21873/anticanres.15416.
Jan-Philipp Ruff  1 ,  Anna-Laura Kretz  1 ,  Marko Kornmann  1 ,  Doris Henne-Bruns  1 ,  Johannes Lemke  2 ,  Benno Traub  1
Affiliations
  • 1. Department of General and Visceral Surgery, University of Ulm, Ulm, Germany.
  • 2. Department of General and Visceral Surgery, University of Ulm, Ulm, Germany [email protected].
PMID: 34848451 DOI: 10.21873/anticanres.15416
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.
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