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The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models

BACKGROUND/AIMS: The therapeutic options for metastatic neuroendocrine tumors (NETs) are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110α inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signali...

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Autores principales: Nölting, Svenja, Rentsch, Jakob, Freitag, Helma, Detjen, Katharina, Briest, Franziska, Möbs, Markus, Weissmann, Victoria, Siegmund, Britta, Auernhammer, Christoph J., Aristizabal Prada, Elke Tatjana, Lauseker, Michael, Grossman, Ashley, Exner, Samantha, Fischer, Christian, Grötzinger, Carsten, Schrader, Jörg, Grabowski, Patricia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553670/
https://www.ncbi.nlm.nih.gov/pubmed/28800359
http://dx.doi.org/10.1371/journal.pone.0182852
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author Nölting, Svenja
Rentsch, Jakob
Freitag, Helma
Detjen, Katharina
Briest, Franziska
Möbs, Markus
Weissmann, Victoria
Siegmund, Britta
Auernhammer, Christoph J.
Aristizabal Prada, Elke Tatjana
Lauseker, Michael
Grossman, Ashley
Exner, Samantha
Fischer, Christian
Grötzinger, Carsten
Schrader, Jörg
Grabowski, Patricia
author_facet Nölting, Svenja
Rentsch, Jakob
Freitag, Helma
Detjen, Katharina
Briest, Franziska
Möbs, Markus
Weissmann, Victoria
Siegmund, Britta
Auernhammer, Christoph J.
Aristizabal Prada, Elke Tatjana
Lauseker, Michael
Grossman, Ashley
Exner, Samantha
Fischer, Christian
Grötzinger, Carsten
Schrader, Jörg
Grabowski, Patricia
author_sort Nölting, Svenja
collection PubMed
description BACKGROUND/AIMS: The therapeutic options for metastatic neuroendocrine tumors (NETs) are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110α inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling pathways, differentiation and secretion in pancreatic (BON-1, QGP-1) and pulmonary (H727) NET cell lines. METHODS: Cell viability was investigated by WST-1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7 assay, the cell cycle by FACS, cell signaling by Western blot analysis, expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and chromogranin A secretion by ELISA. RESULTS: BYL719 dose-dependently decreased cell viability and colony formation with the highest sensitivity in BON-1, followed by H727, and lowest sensitivity in QGP-1 cells. BYL719 induced apoptosis and G0/G1 cell cycle arrest associated with increased p27 expression. Western blots showed inhibition of PI3K downstream targets to a varying degree in the different cell lines, but IGF1R activation. The most sensitive BON-1 cells displayed a significant, and H727 cells a non-significant, GSK3 inhibition after BYL719 treatment, but these effects do not appear to be mediated through the IGF1R. In contrast, the most resistant QGP-1 cells showed no GSK3 inhibition, but a modest activation, which would partially counteract the other anti-proliferative effects. Accordingly, BYL719 enhanced neuroendocrine differentiation with the strongest effect in BON-1, followed by H727 cells indicated by induction of chromogranin A and somatostatin receptor 1/2 mRNA-synthesis, but not in QGP-1 cells. In BON-1 and QGP-1 cells, the BYL719/everolimus combination was synergistic through simultaneous AKT/mTORC1 inhibition, and significantly increased somatostatin receptor 2 transcription compared to each drug separately. CONCLUSION: Our results suggest that the agent BYL719 could be a novel therapeutic approach to the treatment of NETs that may sensitize NET cells to somatostatin analogs, and that if there is resistance to its action this may be overcome by combination with everolimus.
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spelling pubmed-55536702017-08-25 The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models Nölting, Svenja Rentsch, Jakob Freitag, Helma Detjen, Katharina Briest, Franziska Möbs, Markus Weissmann, Victoria Siegmund, Britta Auernhammer, Christoph J. Aristizabal Prada, Elke Tatjana Lauseker, Michael Grossman, Ashley Exner, Samantha Fischer, Christian Grötzinger, Carsten Schrader, Jörg Grabowski, Patricia PLoS One Research Article BACKGROUND/AIMS: The therapeutic options for metastatic neuroendocrine tumors (NETs) are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110α inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling pathways, differentiation and secretion in pancreatic (BON-1, QGP-1) and pulmonary (H727) NET cell lines. METHODS: Cell viability was investigated by WST-1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7 assay, the cell cycle by FACS, cell signaling by Western blot analysis, expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and chromogranin A secretion by ELISA. RESULTS: BYL719 dose-dependently decreased cell viability and colony formation with the highest sensitivity in BON-1, followed by H727, and lowest sensitivity in QGP-1 cells. BYL719 induced apoptosis and G0/G1 cell cycle arrest associated with increased p27 expression. Western blots showed inhibition of PI3K downstream targets to a varying degree in the different cell lines, but IGF1R activation. The most sensitive BON-1 cells displayed a significant, and H727 cells a non-significant, GSK3 inhibition after BYL719 treatment, but these effects do not appear to be mediated through the IGF1R. In contrast, the most resistant QGP-1 cells showed no GSK3 inhibition, but a modest activation, which would partially counteract the other anti-proliferative effects. Accordingly, BYL719 enhanced neuroendocrine differentiation with the strongest effect in BON-1, followed by H727 cells indicated by induction of chromogranin A and somatostatin receptor 1/2 mRNA-synthesis, but not in QGP-1 cells. In BON-1 and QGP-1 cells, the BYL719/everolimus combination was synergistic through simultaneous AKT/mTORC1 inhibition, and significantly increased somatostatin receptor 2 transcription compared to each drug separately. CONCLUSION: Our results suggest that the agent BYL719 could be a novel therapeutic approach to the treatment of NETs that may sensitize NET cells to somatostatin analogs, and that if there is resistance to its action this may be overcome by combination with everolimus. Public Library of Science 2017-08-11 /pmc/articles/PMC5553670/ /pubmed/28800359 http://dx.doi.org/10.1371/journal.pone.0182852 Text en © 2017 Nölting et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Nölting, Svenja
Rentsch, Jakob
Freitag, Helma
Detjen, Katharina
Briest, Franziska
Möbs, Markus
Weissmann, Victoria
Siegmund, Britta
Auernhammer, Christoph J.
Aristizabal Prada, Elke Tatjana
Lauseker, Michael
Grossman, Ashley
Exner, Samantha
Fischer, Christian
Grötzinger, Carsten
Schrader, Jörg
Grabowski, Patricia
The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models
title The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models
title_full The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models
title_fullStr The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models
title_full_unstemmed The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models
title_short The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models
title_sort selective pi3kα inhibitor byl719 as a novel therapeutic option for neuroendocrine tumors: results from multiple cell line models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553670/
https://www.ncbi.nlm.nih.gov/pubmed/28800359
http://dx.doi.org/10.1371/journal.pone.0182852
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