Preclinical validation of 3-phosphoinositide-dependent protein kinase 1 inhibition in pancreatic cancer

J Exp Clin Cancer Res. 2019 May 14;38(1):191. doi: 10.1186/s13046-019-1191-2.


Background: The very aggressive nature and low survival rate of pancreatic ductal adenocarcinoma (PDAC) dictates the necessity to find novel efficacious therapies. Recent evidence suggests that phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1) are key effectors of oncogenic KRAS in PDAC. Herein, we report the role and mechanism of action of PDK1, a protein kinase of the AGC family, in PDAC.

Methods: PDAC cell lines were treated with selective PDK1 inhibitors or transfected with specific PDK1-targeting siRNAs. In vitro and in vivo assays were performed to investigate the functional role of PDK1 in PDAC. Specifically, anchorage-dependent and anchorage-independent growth was assessed in PDAC cells upon inhibition or downregulation of PDK1. Detailed investigation of the effect of PDK1 inhibition/downregulation on specific signalling pathways was also performed by Western blotting analysis. A xenograft tumour mouse model was used to determine the effect of pharmacological inhibition of PDK1 on PDAC cells growth in vivo.

Results: Treatment with specific inhibitors of PDK1 impaired anchorage-dependent and anchorage-independent growth of pancreatic cancer cell lines, as well as pancreatic tumour growth in a xenograft model. Mechanistically, inhibition or downregulation of PDK1 resulted in reduced activation of the serum/glucocorticoid regulated kinase family member 3 and subsequent reduced phosphorylation of its target N-Myc downstream regulated 1. Additionally, we found that combination of sub-optimal concentrations of inhibitors selective for PDK1 and the class IB PI3K isoform p110γ inhibits pancreatic cancer cell growth and colonies formation more potently than each single treatment.

Conclusions: Our data indicate that PDK1 is a suitable target for therapeutic intervention in PDAC and support the clinical development of PDK1 inhibitors for PDAC.

Keywords: 3-phosphoinositide-dependent protein kinase 1; Pancreatic ductal adenocarcinoma; Phosphoinositide 3-kinase; Serum/glucocorticoid regulated kinase family member 3; Signal transduction; Targeted therapy.

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases / antagonists & inhibitors*
  • 3-Phosphoinositide-Dependent Protein Kinases / genetics
  • 3-Phosphoinositide-Dependent Protein Kinases / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Biomarkers
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Humans
  • Mice
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • RNA, Small Interfering / genetics
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Biomarkers
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Phosphatidylinositol 3-Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • PDPK1 protein, human