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...
Autores principales: | , , , , , , , , |
---|---|
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 |