Cargando…

Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma

Agents that target components of the PI3K/AKT/mTOR pathway are under investigation for the treatment of diffuse large B cell lymphoma (DLBCL). Given the highly heterogeneous nature of DLBCL, it is not clear whether all subtypes of DLBCL will be susceptible to PI3K pathway inhibition, or which kinase...

Descripción completa

Detalles Bibliográficos
Autores principales: Ezell, Scott A., Wang, Suping, Bihani, Teeru, Lai, Zhongwu, Grosskurth, Shaun E., Tepsuporn, Suprawee, Davies, Barry R., Huszar, Dennis, Byth, Kate F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891033/
https://www.ncbi.nlm.nih.gov/pubmed/26824321
http://dx.doi.org/10.18632/oncotarget.7036
_version_ 1782435206400049152
author Ezell, Scott A.
Wang, Suping
Bihani, Teeru
Lai, Zhongwu
Grosskurth, Shaun E.
Tepsuporn, Suprawee
Davies, Barry R.
Huszar, Dennis
Byth, Kate F.
author_facet Ezell, Scott A.
Wang, Suping
Bihani, Teeru
Lai, Zhongwu
Grosskurth, Shaun E.
Tepsuporn, Suprawee
Davies, Barry R.
Huszar, Dennis
Byth, Kate F.
author_sort Ezell, Scott A.
collection PubMed
description Agents that target components of the PI3K/AKT/mTOR pathway are under investigation for the treatment of diffuse large B cell lymphoma (DLBCL). Given the highly heterogeneous nature of DLBCL, it is not clear whether all subtypes of DLBCL will be susceptible to PI3K pathway inhibition, or which kinase within this pathway is the most favorable target. Pharmacological profiling of a panel of DLBCL cell lines revealed a subset of DLBCL that was resistant to AKT inhibition. Strikingly, sensitivity to AKT inhibitors correlated with the ability of these inhibitors to block phosphorylation of S6K1 and ribosomal protein S6. Cell lines resistant to AKT inhibition activated S6K1 independent of AKT either through upregulation of PIM2 or through activation by B cell receptor (BCR) signaling components. Finally, combined inhibition of AKT and BTK, PIM2, or S6K1 proved to be an effective strategy to overcome resistance to AKT inhibition in DLBCL.
format Online
Article
Text
id pubmed-4891033
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-48910332016-06-20 Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma Ezell, Scott A. Wang, Suping Bihani, Teeru Lai, Zhongwu Grosskurth, Shaun E. Tepsuporn, Suprawee Davies, Barry R. Huszar, Dennis Byth, Kate F. Oncotarget Research Paper Agents that target components of the PI3K/AKT/mTOR pathway are under investigation for the treatment of diffuse large B cell lymphoma (DLBCL). Given the highly heterogeneous nature of DLBCL, it is not clear whether all subtypes of DLBCL will be susceptible to PI3K pathway inhibition, or which kinase within this pathway is the most favorable target. Pharmacological profiling of a panel of DLBCL cell lines revealed a subset of DLBCL that was resistant to AKT inhibition. Strikingly, sensitivity to AKT inhibitors correlated with the ability of these inhibitors to block phosphorylation of S6K1 and ribosomal protein S6. Cell lines resistant to AKT inhibition activated S6K1 independent of AKT either through upregulation of PIM2 or through activation by B cell receptor (BCR) signaling components. Finally, combined inhibition of AKT and BTK, PIM2, or S6K1 proved to be an effective strategy to overcome resistance to AKT inhibition in DLBCL. Impact Journals LLC 2016-01-27 /pmc/articles/PMC4891033/ /pubmed/26824321 http://dx.doi.org/10.18632/oncotarget.7036 Text en Copyright: © 2016 Ezell et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Ezell, Scott A.
Wang, Suping
Bihani, Teeru
Lai, Zhongwu
Grosskurth, Shaun E.
Tepsuporn, Suprawee
Davies, Barry R.
Huszar, Dennis
Byth, Kate F.
Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma
title Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma
title_full Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma
title_fullStr Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma
title_full_unstemmed Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma
title_short Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma
title_sort differential regulation of mtor signaling determines sensitivity to akt inhibition in diffuse large b cell lymphoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891033/
https://www.ncbi.nlm.nih.gov/pubmed/26824321
http://dx.doi.org/10.18632/oncotarget.7036
work_keys_str_mv AT ezellscotta differentialregulationofmtorsignalingdeterminessensitivitytoaktinhibitionindiffuselargebcelllymphoma
AT wangsuping differentialregulationofmtorsignalingdeterminessensitivitytoaktinhibitionindiffuselargebcelllymphoma
AT bihaniteeru differentialregulationofmtorsignalingdeterminessensitivitytoaktinhibitionindiffuselargebcelllymphoma
AT laizhongwu differentialregulationofmtorsignalingdeterminessensitivitytoaktinhibitionindiffuselargebcelllymphoma
AT grosskurthshaune differentialregulationofmtorsignalingdeterminessensitivitytoaktinhibitionindiffuselargebcelllymphoma
AT tepsupornsuprawee differentialregulationofmtorsignalingdeterminessensitivitytoaktinhibitionindiffuselargebcelllymphoma
AT daviesbarryr differentialregulationofmtorsignalingdeterminessensitivitytoaktinhibitionindiffuselargebcelllymphoma
AT huszardennis differentialregulationofmtorsignalingdeterminessensitivitytoaktinhibitionindiffuselargebcelllymphoma
AT bythkatef differentialregulationofmtorsignalingdeterminessensitivitytoaktinhibitionindiffuselargebcelllymphoma