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Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma
Undifferentiated pleomorphic sarcomas (UPSs) are aggressive mesenchymal malignancies with no definitive cell of origin or specific recurrent genetic hallmarks. These tumors are largely chemoresistant; thus, identification of potential therapeutic targets is necessary to improve patient outcome. Prev...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678691/ https://www.ncbi.nlm.nih.gov/pubmed/29099264 http://dx.doi.org/10.1080/15384047.2017.1373230 |
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author | May, Caitlin D. Landers, Sharon M. Bolshakov, Svetlana Ma, XiaoYan Ingram, Davis R. Kivlin, Christine M. Watson, Kelsey L. Sannaa, Ghadah A. Al Bhalla, Angela D. Wang, Wei-Lien Lazar, Alexander J. Torres, Keila E. |
author_facet | May, Caitlin D. Landers, Sharon M. Bolshakov, Svetlana Ma, XiaoYan Ingram, Davis R. Kivlin, Christine M. Watson, Kelsey L. Sannaa, Ghadah A. Al Bhalla, Angela D. Wang, Wei-Lien Lazar, Alexander J. Torres, Keila E. |
author_sort | May, Caitlin D. |
collection | PubMed |
description | Undifferentiated pleomorphic sarcomas (UPSs) are aggressive mesenchymal malignancies with no definitive cell of origin or specific recurrent genetic hallmarks. These tumors are largely chemoresistant; thus, identification of potential therapeutic targets is necessary to improve patient outcome. Previous studies demonstrated that high expression of activated protein kinase B (AKT) in patients with UPS corresponds to poor disease-specific survival. Here, we demonstrate that inhibiting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling using a small molecule inhibitor reduced UPS cell proliferation and motility and xenograft growth; however, increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) indicated the potential for adaptive resistance following treatment through compensatory receptor activation. Co-treatment with a dual PI3K/mTOR inhibitor and an anti-IGF1R kinase inhibitor reduced in vivo tumor growth rates despite a lack of antiproliferative effects in vitro. Moreover, this combination treatment significantly decreased UPS cell migration and invasion, which is linked to changes in p27 subcellular localization. Our results demonstrate that targeted inhibition of multiple components of the IGF1R/PI3K/mTOR pathway was more efficacious than single-agent therapy and suggest that co-targeting this pathway could be a beneficial therapeutic strategy for patients with UPS. |
format | Online Article Text |
id | pubmed-5678691 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-56786912017-11-17 Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma May, Caitlin D. Landers, Sharon M. Bolshakov, Svetlana Ma, XiaoYan Ingram, Davis R. Kivlin, Christine M. Watson, Kelsey L. Sannaa, Ghadah A. Al Bhalla, Angela D. Wang, Wei-Lien Lazar, Alexander J. Torres, Keila E. Cancer Biol Ther Research Paper Undifferentiated pleomorphic sarcomas (UPSs) are aggressive mesenchymal malignancies with no definitive cell of origin or specific recurrent genetic hallmarks. These tumors are largely chemoresistant; thus, identification of potential therapeutic targets is necessary to improve patient outcome. Previous studies demonstrated that high expression of activated protein kinase B (AKT) in patients with UPS corresponds to poor disease-specific survival. Here, we demonstrate that inhibiting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling using a small molecule inhibitor reduced UPS cell proliferation and motility and xenograft growth; however, increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) indicated the potential for adaptive resistance following treatment through compensatory receptor activation. Co-treatment with a dual PI3K/mTOR inhibitor and an anti-IGF1R kinase inhibitor reduced in vivo tumor growth rates despite a lack of antiproliferative effects in vitro. Moreover, this combination treatment significantly decreased UPS cell migration and invasion, which is linked to changes in p27 subcellular localization. Our results demonstrate that targeted inhibition of multiple components of the IGF1R/PI3K/mTOR pathway was more efficacious than single-agent therapy and suggest that co-targeting this pathway could be a beneficial therapeutic strategy for patients with UPS. Taylor & Francis 2017-11-03 /pmc/articles/PMC5678691/ /pubmed/29099264 http://dx.doi.org/10.1080/15384047.2017.1373230 Text en © 2017 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License http://creativecommons.org/licenses/by-nc-nd/4.0/, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. |
spellingShingle | Research Paper May, Caitlin D. Landers, Sharon M. Bolshakov, Svetlana Ma, XiaoYan Ingram, Davis R. Kivlin, Christine M. Watson, Kelsey L. Sannaa, Ghadah A. Al Bhalla, Angela D. Wang, Wei-Lien Lazar, Alexander J. Torres, Keila E. Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma |
title | Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma |
title_full | Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma |
title_fullStr | Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma |
title_full_unstemmed | Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma |
title_short | Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma |
title_sort | co-targeting pi3k, mtor, and igf1r with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678691/ https://www.ncbi.nlm.nih.gov/pubmed/29099264 http://dx.doi.org/10.1080/15384047.2017.1373230 |
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