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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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