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

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

Author information

1
Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia.
2
Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, E1 2AT, London, UK.
3
Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University G. d'Annunzio di Chieti-Pescara, Centro Studi sull Invecchiamento, CeSI-MeT, 66100, Chieti, Italy.
4
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126, Pisa, Italy.
5
MediaPharma Srl, Via della Colonnetta, 50/A, 66100, Chieti, Italy.
6
Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia. marco.falasca@curtin.edu.au.
7
Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, E1 2AT, London, UK. marco.falasca@curtin.edu.au.

Abstract

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

PMID:
31088502
PMCID:
PMC6518649
DOI:
10.1186/s13046-019-1191-2
[Indexed for MEDLINE]
Free PMC Article

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