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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy with limited treatment options.
• Novel therapeutic strategies are urgently needed to overcome resistance and improve patient outcomes.

Purpose of the Study:

• To investigate the efficacy of combining Atuveciclib, an orally bioavailable CDK9-inhibitor, with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
• To evaluate the impact of this combination therapy on pancreatic cancer cells, including gemcitabine-resistant and patient-derived models.

Main Methods:

• Cell viability was assessed using MTT assays.
• Colony formation potential was evaluated.
• Apoptosis and cell-cycle arrest were analyzed via flow cytometry.
• Protein expression levels of key regulatory molecules were determined by western blot analysis.

Main Results:

• The combination of Atuveciclib and TRAIL significantly inhibited pancreatic cancer cell viability and colony formation.
• This synergistic effect was mediated by the induction of apoptosis and cell-cycle arrest.
• Atuveciclib sensitized PDAC cells to TRAIL-induced apoptosis by suppressing cFlip and Mcl-1.
• The combination therapy demonstrated efficacy in gemcitabine-resistant PDAC cell lines and patient-derived xenograft (PDX) models.

Conclusions:

• The combined treatment of Atuveciclib and TRAIL shows significant preclinical efficacy against pancreatic cancer.
• This combination therapy warrants further investigation in preclinical and clinical settings for PDAC treatment.