Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer

Abstract PIM and PI3K/mTOR pathways are often dysregulated in prostate cancer, and may lead to decreased survival, increased metastasis and invasion. The pathways are heavily interconnected and act on a variety of common effectors that can lead to the development of resistance to drug inhibitors. Mo...

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Autores principales:	Sabina Luszczak, Benjamin S. Simpson, Urszula Stopka-Farooqui, Vignesh Krishna Sathyadevan, Lina M. Carmona Echeverria, Christopher Kumar, Helena Costa, Aiman Haider, Alex Freeman, Charles Jameson, Marzena Ratynska, Imen Ben-Salha, Ashwin Sridhar, Greg Shaw, John D. Kelly, Hayley Pye, Kathy A. Gately, Hayley C. Whitaker, Susan Heavey
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5720892a10484524bbddcc6413152966
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spelling	oai:doaj.org-article:5720892a10484524bbddcc64131529662021-12-02T19:04:25ZCo-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer10.1038/s41598-020-71263-92045-2322https://doaj.org/article/5720892a10484524bbddcc64131529662020-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-71263-9https://doaj.org/toc/2045-2322Abstract PIM and PI3K/mTOR pathways are often dysregulated in prostate cancer, and may lead to decreased survival, increased metastasis and invasion. The pathways are heavily interconnected and act on a variety of common effectors that can lead to the development of resistance to drug inhibitors. Most current treatments exhibit issues with toxicity and resistance. We investigated the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, versus a combination of the PIM inhibitor, AZD-1208, and the PI3K/mTOR inhibitor BEZ235 (Dactolisib) to determine their impact on mRNA and phosphoprotein expression, as well as their functional efficacy. We have determined that around 20% of prostate cancer patients overexpress the direct targets of these drugs, and this cohort are more likely to have a high Gleason grade tumour (≥ Gleason 8). A co-targeted inhibition approach offered broader inhibition of genes and phosphoproteins in the PI3K/mTOR pathway, when compared to single kinase inhibition. The preclinical inhibitor AUM302, used at a lower dose, elicited a comparable or superior functional outcome compared with combined AZD-1208 + BEZ235, which have been investigated in clinical trials, and could help to reduce treatment toxicity in future trials. We believe that a co-targeting approach is a viable therapeutic strategy that should be developed further in pre-clinical studies.Sabina LuszczakBenjamin S. SimpsonUrszula Stopka-FarooquiVignesh Krishna SathyadevanLina M. Carmona EcheverriaChristopher KumarHelena CostaAiman HaiderAlex FreemanCharles JamesonMarzena RatynskaImen Ben-SalhaAshwin SridharGreg ShawJohn D. KellyHayley PyeKathy A. GatelyHayley C. WhitakerSusan HeaveyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sabina Luszczak Benjamin S. Simpson Urszula Stopka-Farooqui Vignesh Krishna Sathyadevan Lina M. Carmona Echeverria Christopher Kumar Helena Costa Aiman Haider Alex Freeman Charles Jameson Marzena Ratynska Imen Ben-Salha Ashwin Sridhar Greg Shaw John D. Kelly Hayley Pye Kathy A. Gately Hayley C. Whitaker Susan Heavey Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer
description	Abstract PIM and PI3K/mTOR pathways are often dysregulated in prostate cancer, and may lead to decreased survival, increased metastasis and invasion. The pathways are heavily interconnected and act on a variety of common effectors that can lead to the development of resistance to drug inhibitors. Most current treatments exhibit issues with toxicity and resistance. We investigated the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, versus a combination of the PIM inhibitor, AZD-1208, and the PI3K/mTOR inhibitor BEZ235 (Dactolisib) to determine their impact on mRNA and phosphoprotein expression, as well as their functional efficacy. We have determined that around 20% of prostate cancer patients overexpress the direct targets of these drugs, and this cohort are more likely to have a high Gleason grade tumour (≥ Gleason 8). A co-targeted inhibition approach offered broader inhibition of genes and phosphoproteins in the PI3K/mTOR pathway, when compared to single kinase inhibition. The preclinical inhibitor AUM302, used at a lower dose, elicited a comparable or superior functional outcome compared with combined AZD-1208 + BEZ235, which have been investigated in clinical trials, and could help to reduce treatment toxicity in future trials. We believe that a co-targeting approach is a viable therapeutic strategy that should be developed further in pre-clinical studies.
format	article
author	Sabina Luszczak Benjamin S. Simpson Urszula Stopka-Farooqui Vignesh Krishna Sathyadevan Lina M. Carmona Echeverria Christopher Kumar Helena Costa Aiman Haider Alex Freeman Charles Jameson Marzena Ratynska Imen Ben-Salha Ashwin Sridhar Greg Shaw John D. Kelly Hayley Pye Kathy A. Gately Hayley C. Whitaker Susan Heavey
author_facet	Sabina Luszczak Benjamin S. Simpson Urszula Stopka-Farooqui Vignesh Krishna Sathyadevan Lina M. Carmona Echeverria Christopher Kumar Helena Costa Aiman Haider Alex Freeman Charles Jameson Marzena Ratynska Imen Ben-Salha Ashwin Sridhar Greg Shaw John D. Kelly Hayley Pye Kathy A. Gately Hayley C. Whitaker Susan Heavey
author_sort	Sabina Luszczak
title	Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer
title_short	Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer
title_full	Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer
title_fullStr	Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer
title_full_unstemmed	Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer
title_sort	co-targeting pim and pi3k/mtor using multikinase inhibitor aum302 and a combination of azd-1208 and bez235 in prostate cancer
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/5720892a10484524bbddcc6413152966
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Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer

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