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Dual Targeting of EGFR and MTOR Pathways Inhibits Glioblastoma Growth by Modulating the Tumor Microenvironment
Glioblastoma’s (GBM) aggressive growth is driven by redundant activation of a myriad of signaling pathways and genomic alterations in tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), which is altered in over 50% of cases. Single agents targeting EGFR have not proven effect...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954001/ https://www.ncbi.nlm.nih.gov/pubmed/36831214 http://dx.doi.org/10.3390/cells12040547 |
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author | Sidorov, Maxim Dighe, Pratiksha Woo, Rinette W. L. Rodriguez-Brotons, Aida Chen, Michelle Ice, Ryan J. Vaquero, Edith Jian, Damon Desprez, Pierre-Yves Nosrati, Mehdi Galvez, Leah Leng, Lewis Dickinson, Lawrence Kashani-Sabet, Mohammed McAllister, Sean David Soroceanu, Liliana |
author_facet | Sidorov, Maxim Dighe, Pratiksha Woo, Rinette W. L. Rodriguez-Brotons, Aida Chen, Michelle Ice, Ryan J. Vaquero, Edith Jian, Damon Desprez, Pierre-Yves Nosrati, Mehdi Galvez, Leah Leng, Lewis Dickinson, Lawrence Kashani-Sabet, Mohammed McAllister, Sean David Soroceanu, Liliana |
author_sort | Sidorov, Maxim |
collection | PubMed |
description | Glioblastoma’s (GBM) aggressive growth is driven by redundant activation of a myriad of signaling pathways and genomic alterations in tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), which is altered in over 50% of cases. Single agents targeting EGFR have not proven effective against GBM. In this study, we aimed to identify an effective anti-tumor regimen using pharmacogenomic testing of patient-derived GBM samples, in culture and in vivo. High-throughput pharmacological screens of ten EGFR-driven GBM samples identified the combination of erlotinib (EGFRi) and MLN0128 (a mammalian target of rapamycin inhibitor, or MTORi) as the most effective at inhibiting tumor cell viability. The anti-tumor activity of erlonitib+MLN0128 was synergistic and produced inhibition of the p-EGFR, mitogen-activated protein kinase (MAPK), and Phosphoinositide 3-kinase (PI3K) pathways in culture. Using an orthotopic murine model of GBM, we show that erlotinib+MLN0128 inhibited tumor growth in vivo and significantly prolonged the survival of tumor-bearing mice. Expression profiling of tumor tissues from treated mice revealed a unique gene signature induced by erlotinib+MLN0128, consisting of downregulation of immunosuppressive chemokines in the tumor microenvironment, including C-C motif chemokine ligand 2 (CCL2) and periostin. Lower periostin levels resulted in the inhibition of Iba1+ (tumor-promoting) macrophage infiltration of GBM xenografts. Taken together, our results demonstrate that pharmacological co-targeting of EGFR and MTOR using clinically available drugs represents an effective treatment paradigm for EGFR-driven GBMs, acting both by inhibiting tumor cell growth and modulating the immune tumor microenvironment. |
format | Online Article Text |
id | pubmed-9954001 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99540012023-02-25 Dual Targeting of EGFR and MTOR Pathways Inhibits Glioblastoma Growth by Modulating the Tumor Microenvironment Sidorov, Maxim Dighe, Pratiksha Woo, Rinette W. L. Rodriguez-Brotons, Aida Chen, Michelle Ice, Ryan J. Vaquero, Edith Jian, Damon Desprez, Pierre-Yves Nosrati, Mehdi Galvez, Leah Leng, Lewis Dickinson, Lawrence Kashani-Sabet, Mohammed McAllister, Sean David Soroceanu, Liliana Cells Article Glioblastoma’s (GBM) aggressive growth is driven by redundant activation of a myriad of signaling pathways and genomic alterations in tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), which is altered in over 50% of cases. Single agents targeting EGFR have not proven effective against GBM. In this study, we aimed to identify an effective anti-tumor regimen using pharmacogenomic testing of patient-derived GBM samples, in culture and in vivo. High-throughput pharmacological screens of ten EGFR-driven GBM samples identified the combination of erlotinib (EGFRi) and MLN0128 (a mammalian target of rapamycin inhibitor, or MTORi) as the most effective at inhibiting tumor cell viability. The anti-tumor activity of erlonitib+MLN0128 was synergistic and produced inhibition of the p-EGFR, mitogen-activated protein kinase (MAPK), and Phosphoinositide 3-kinase (PI3K) pathways in culture. Using an orthotopic murine model of GBM, we show that erlotinib+MLN0128 inhibited tumor growth in vivo and significantly prolonged the survival of tumor-bearing mice. Expression profiling of tumor tissues from treated mice revealed a unique gene signature induced by erlotinib+MLN0128, consisting of downregulation of immunosuppressive chemokines in the tumor microenvironment, including C-C motif chemokine ligand 2 (CCL2) and periostin. Lower periostin levels resulted in the inhibition of Iba1+ (tumor-promoting) macrophage infiltration of GBM xenografts. Taken together, our results demonstrate that pharmacological co-targeting of EGFR and MTOR using clinically available drugs represents an effective treatment paradigm for EGFR-driven GBMs, acting both by inhibiting tumor cell growth and modulating the immune tumor microenvironment. MDPI 2023-02-08 /pmc/articles/PMC9954001/ /pubmed/36831214 http://dx.doi.org/10.3390/cells12040547 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sidorov, Maxim Dighe, Pratiksha Woo, Rinette W. L. Rodriguez-Brotons, Aida Chen, Michelle Ice, Ryan J. Vaquero, Edith Jian, Damon Desprez, Pierre-Yves Nosrati, Mehdi Galvez, Leah Leng, Lewis Dickinson, Lawrence Kashani-Sabet, Mohammed McAllister, Sean David Soroceanu, Liliana Dual Targeting of EGFR and MTOR Pathways Inhibits Glioblastoma Growth by Modulating the Tumor Microenvironment |
title | Dual Targeting of EGFR and MTOR Pathways Inhibits Glioblastoma Growth by Modulating the Tumor Microenvironment |
title_full | Dual Targeting of EGFR and MTOR Pathways Inhibits Glioblastoma Growth by Modulating the Tumor Microenvironment |
title_fullStr | Dual Targeting of EGFR and MTOR Pathways Inhibits Glioblastoma Growth by Modulating the Tumor Microenvironment |
title_full_unstemmed | Dual Targeting of EGFR and MTOR Pathways Inhibits Glioblastoma Growth by Modulating the Tumor Microenvironment |
title_short | Dual Targeting of EGFR and MTOR Pathways Inhibits Glioblastoma Growth by Modulating the Tumor Microenvironment |
title_sort | dual targeting of egfr and mtor pathways inhibits glioblastoma growth by modulating the tumor microenvironment |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954001/ https://www.ncbi.nlm.nih.gov/pubmed/36831214 http://dx.doi.org/10.3390/cells12040547 |
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