RESUMO
The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC's resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.
Assuntos
Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/metabolismo , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Ciclo Celular/genética , Ensaios Clínicos como Assunto , Quinases Ciclina-Dependentes/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Família Multigênica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais , Transcrição Gênica , Neoplasias PancreáticasRESUMO
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.