Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC
PIM kinases are constitutively active proto-oncogenic serine/threonine kinases that play a role in cell cycle progression, metabolism, inflammation and drug resistance. PIM kinases interact with and stabilize p53, c-Myc and parallel signaling pathway PI3K/Akt. This study evaluated PIM kinase express...
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Online Access: | https://www.mdpi.com/2072-6694/13/9/2139 |
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doaj-1d73af4dcbaa4b6291be07d7d9eeb0dd2021-04-29T23:01:44ZengMDPI AGCancers2072-66942021-04-01132139213910.3390/cancers13092139Co-Targeting PIM Kinase and PI3K/mTOR in NSCLCGillian Moore0Clara Lightner1Samira Elbai2Lauren Brady3Siobhan Nicholson4Ronan Ryan5Katie E. O’Sullivan6Kenneth J. O’Byrne7Carmen Blanco-Apiricio8Sinead Cuffe9Michael O’Neill10Susan Heavey11Stephen P. Finn12Kathy Gately13Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Dublin, IrelandDepartment of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Dublin, IrelandDepartment of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Dublin, IrelandDepartment of Histopathology, St. James’s Hospital, Dublin, IrelandDepartment of Histopathology, St. James’s Hospital, Dublin, IrelandDepartment of Cardio-Thoracic Surgery, St. James’s Hospital, Dublin, IrelandDepartment of Cardio-Thoracic Surgery, St. James’s Hospital, Dublin, IrelandPrincess Alexandra Hospital, Translational Research Institute and The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4102, AustraliaExperimental Therapeutics Program, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, 28029 Madrid, SpainDepartment of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Dublin, IrelandInflection Biosciences Ltd., Blackrock Co., Dublin, IrelandDivision of Surgery and Interventional Science, University College London, London WC1E 6BT, UKDepartment of Histopathology, St. James’s Hospital, Dublin, IrelandDepartment of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Dublin, IrelandPIM kinases are constitutively active proto-oncogenic serine/threonine kinases that play a role in cell cycle progression, metabolism, inflammation and drug resistance. PIM kinases interact with and stabilize p53, c-Myc and parallel signaling pathway PI3K/Akt. This study evaluated PIM kinase expression in NSCLC and in response to PI3K/mTOR inhibition. It investigated a novel preclinical PI3K/mTOR/PIM inhibitor (IBL-301) in vitro and in patient-derived NSCLC tumor tissues. Western blot analysis confirmed PIM1, PIM2 and PIM3 are expressed in NSCLC cell lines and PIM1 is a marker of poor prognosis in patients with NSCLC. IBL-301 decreased PIM1, c-Myc, pBAD and p4EBP1 (Thr37/46) and peIF4B (S406) protein levels in-vitro and MAP kinase, PI3K-Akt and JAK/STAT pathways in tumor tissue explants. IBL-301 significantly decreased secreted pro-inflammatory cytokine MCP-1. Altered mRNA expression, including activated PIM kinase and c-Myc, was identified in Apitolisib resistant cells (H1975GR) by an IL-6/STAT3 pathway array and validated by Western blot. H1975GR cells were more sensitive to IBL-301 than parent cells. A miRNA array identified a dysregulated miRNA signature of PI3K/mTOR drug resistance consisting of regulators of PIM kinase and c-Myc (miR17-5p, miR19b-3p, miR20a-5p, miR15b-5p, miR203a, miR-206). Our data provides a rationale for co-targeting PIM kinase and PI3K-mTOR to improve therapeutic response in NSCLC.https://www.mdpi.com/2072-6694/13/9/2139PIM kinasePI3K-mTORc-Mycdrug resistanceNSCLCtumor tissue explants |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gillian Moore Clara Lightner Samira Elbai Lauren Brady Siobhan Nicholson Ronan Ryan Katie E. O’Sullivan Kenneth J. O’Byrne Carmen Blanco-Apiricio Sinead Cuffe Michael O’Neill Susan Heavey Stephen P. Finn Kathy Gately |
spellingShingle |
Gillian Moore Clara Lightner Samira Elbai Lauren Brady Siobhan Nicholson Ronan Ryan Katie E. O’Sullivan Kenneth J. O’Byrne Carmen Blanco-Apiricio Sinead Cuffe Michael O’Neill Susan Heavey Stephen P. Finn Kathy Gately Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC Cancers PIM kinase PI3K-mTOR c-Myc drug resistance NSCLC tumor tissue explants |
author_facet |
Gillian Moore Clara Lightner Samira Elbai Lauren Brady Siobhan Nicholson Ronan Ryan Katie E. O’Sullivan Kenneth J. O’Byrne Carmen Blanco-Apiricio Sinead Cuffe Michael O’Neill Susan Heavey Stephen P. Finn Kathy Gately |
author_sort |
Gillian Moore |
title |
Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC |
title_short |
Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC |
title_full |
Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC |
title_fullStr |
Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC |
title_full_unstemmed |
Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC |
title_sort |
co-targeting pim kinase and pi3k/mtor in nsclc |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-04-01 |
description |
PIM kinases are constitutively active proto-oncogenic serine/threonine kinases that play a role in cell cycle progression, metabolism, inflammation and drug resistance. PIM kinases interact with and stabilize p53, c-Myc and parallel signaling pathway PI3K/Akt. This study evaluated PIM kinase expression in NSCLC and in response to PI3K/mTOR inhibition. It investigated a novel preclinical PI3K/mTOR/PIM inhibitor (IBL-301) in vitro and in patient-derived NSCLC tumor tissues. Western blot analysis confirmed PIM1, PIM2 and PIM3 are expressed in NSCLC cell lines and PIM1 is a marker of poor prognosis in patients with NSCLC. IBL-301 decreased PIM1, c-Myc, pBAD and p4EBP1 (Thr37/46) and peIF4B (S406) protein levels in-vitro and MAP kinase, PI3K-Akt and JAK/STAT pathways in tumor tissue explants. IBL-301 significantly decreased secreted pro-inflammatory cytokine MCP-1. Altered mRNA expression, including activated PIM kinase and c-Myc, was identified in Apitolisib resistant cells (H1975GR) by an IL-6/STAT3 pathway array and validated by Western blot. H1975GR cells were more sensitive to IBL-301 than parent cells. A miRNA array identified a dysregulated miRNA signature of PI3K/mTOR drug resistance consisting of regulators of PIM kinase and c-Myc (miR17-5p, miR19b-3p, miR20a-5p, miR15b-5p, miR203a, miR-206). Our data provides a rationale for co-targeting PIM kinase and PI3K-mTOR to improve therapeutic response in NSCLC. |
topic |
PIM kinase PI3K-mTOR c-Myc drug resistance NSCLC tumor tissue explants |
url |
https://www.mdpi.com/2072-6694/13/9/2139 |
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