Cargando…

Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML

Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the F...

Descripción completa

Detalles Bibliográficos
Autores principales: Lindblad, O, Cordero, E, Puissant, A, Macaulay, L, Ramos, A, Kabir, N N, Sun, J, Vallon-Christersson, J, Haraldsson, K, Hemann, M T, Borg, Å, Levander, F, Stegmaier, K, Pietras, K, Rönnstrand, L, Kazi, J U
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399143/
https://www.ncbi.nlm.nih.gov/pubmed/26999641
http://dx.doi.org/10.1038/onc.2016.41
_version_ 1783230577898422272
author Lindblad, O
Cordero, E
Puissant, A
Macaulay, L
Ramos, A
Kabir, N N
Sun, J
Vallon-Christersson, J
Haraldsson, K
Hemann, M T
Borg, Å
Levander, F
Stegmaier, K
Pietras, K
Rönnstrand, L
Kazi, J U
author_facet Lindblad, O
Cordero, E
Puissant, A
Macaulay, L
Ramos, A
Kabir, N N
Sun, J
Vallon-Christersson, J
Haraldsson, K
Hemann, M T
Borg, Å
Levander, F
Stegmaier, K
Pietras, K
Rönnstrand, L
Kazi, J U
author_sort Lindblad, O
collection PubMed
description Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors. Sanger sequencing and protein mass-spectrometry did not identify any acquired mutations in FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer FLT3 dependent. Gene expression analysis of sensitive and resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway in the resistant phenotype, which was further supported by next-generation sequencing and phospho-specific-antibody array analysis. Furthermore, a selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation, and induced apoptosis in resistant cell lines. Gedatolisib significantly extended survival of mice in a sorafenib-resistant AML patient-derived xenograft model. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs targeting FLT3.
format Online
Article
Text
id pubmed-5399143
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-53991432017-05-09 Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML Lindblad, O Cordero, E Puissant, A Macaulay, L Ramos, A Kabir, N N Sun, J Vallon-Christersson, J Haraldsson, K Hemann, M T Borg, Å Levander, F Stegmaier, K Pietras, K Rönnstrand, L Kazi, J U Oncogene Original Article Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors. Sanger sequencing and protein mass-spectrometry did not identify any acquired mutations in FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer FLT3 dependent. Gene expression analysis of sensitive and resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway in the resistant phenotype, which was further supported by next-generation sequencing and phospho-specific-antibody array analysis. Furthermore, a selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation, and induced apoptosis in resistant cell lines. Gedatolisib significantly extended survival of mice in a sorafenib-resistant AML patient-derived xenograft model. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs targeting FLT3. Nature Publishing Group 2016-09-29 2016-03-21 /pmc/articles/PMC5399143/ /pubmed/26999641 http://dx.doi.org/10.1038/onc.2016.41 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Lindblad, O
Cordero, E
Puissant, A
Macaulay, L
Ramos, A
Kabir, N N
Sun, J
Vallon-Christersson, J
Haraldsson, K
Hemann, M T
Borg, Å
Levander, F
Stegmaier, K
Pietras, K
Rönnstrand, L
Kazi, J U
Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML
title Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML
title_full Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML
title_fullStr Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML
title_full_unstemmed Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML
title_short Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML
title_sort aberrant activation of the pi3k/mtor pathway promotes resistance to sorafenib in aml
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399143/
https://www.ncbi.nlm.nih.gov/pubmed/26999641
http://dx.doi.org/10.1038/onc.2016.41
work_keys_str_mv AT lindblado aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT corderoe aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT puissanta aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT macaulayl aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT ramosa aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT kabirnn aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT sunj aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT vallonchristerssonj aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT haraldssonk aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT hemannmt aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT borga aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT levanderf aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT stegmaierk aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT pietrask aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT ronnstrandl aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml
AT kaziju aberrantactivationofthepi3kmtorpathwaypromotesresistancetosorafenibinaml