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Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma

BACKGROUND: Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients. However, the problem is that tumors frequently acquire resistance to the treatment. To understand the underlyi...

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Autores principales: Krausert, Sonja, Brabetz, Sebastian, Mack, Norman L, Schmitt-Hoffner, Felix, Schwalm, Benjamin, Peterziel, Heike, Mangang, Aileen, Holland-Letz, Tim, Sieber, Laura, Korshunov, Andrey, Oehme, Ina, Jäger, Natalie, Witt, Olaf, Pfister, Stefan M, Kool, Marcel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034118/
https://www.ncbi.nlm.nih.gov/pubmed/35475274
http://dx.doi.org/10.1093/noajnl/vdac026
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author Krausert, Sonja
Brabetz, Sebastian
Mack, Norman L
Schmitt-Hoffner, Felix
Schwalm, Benjamin
Peterziel, Heike
Mangang, Aileen
Holland-Letz, Tim
Sieber, Laura
Korshunov, Andrey
Oehme, Ina
Jäger, Natalie
Witt, Olaf
Pfister, Stefan M
Kool, Marcel
author_facet Krausert, Sonja
Brabetz, Sebastian
Mack, Norman L
Schmitt-Hoffner, Felix
Schwalm, Benjamin
Peterziel, Heike
Mangang, Aileen
Holland-Letz, Tim
Sieber, Laura
Korshunov, Andrey
Oehme, Ina
Jäger, Natalie
Witt, Olaf
Pfister, Stefan M
Kool, Marcel
author_sort Krausert, Sonja
collection PubMed
description BACKGROUND: Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients. However, the problem is that tumors frequently acquire resistance to the treatment. To understand the underlying resistance mechanisms and to find ways to overcome the resistance, preclinical models that became resistant to SMO inhibition are needed. METHODS: To induce SMO inhibitor resistant tumors, we have treated a patient-derived xenograft (PDX) model of SHH medulloblastoma, sensitive to SMO inhibition, with 20 mg/kg Sonidegib using an intermitted treatment schedule. Vehicle-treated and resistant models were subjected to whole-genome and RNA sequencing for molecular characterization and target engagement. In vitro drug screens (76 drugs) were performed using Sonidegib-sensitive and -resistant lines to find other drugs to target the resistant lines. One of the top hits was then validated in vivo. RESULTS: Nine independent Sonidegib-resistant PDX lines were generated. Molecular characterization of the resistant models showed that eight models developed missense mutations in SMO and one gained an inactivating point mutation in MEGF8, which acts downstream of SMO as a repressor in the SHH pathway. The in vitro drug screen with Sonidegib-sensitive and -resistant lines identified good efficacy for Selinexor in the resistant line. Indeed, in vivo treatment with Selinexor revealed that it is more effective in resistant than in sensitive models. CONCLUSIONS: We report the first human SMO inhibitor resistant medulloblastoma PDX models, which can be used for further preclinical experiments to develop the best strategies to overcome the resistance to SMO inhibitors in patients.
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spelling pubmed-90341182022-04-25 Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma Krausert, Sonja Brabetz, Sebastian Mack, Norman L Schmitt-Hoffner, Felix Schwalm, Benjamin Peterziel, Heike Mangang, Aileen Holland-Letz, Tim Sieber, Laura Korshunov, Andrey Oehme, Ina Jäger, Natalie Witt, Olaf Pfister, Stefan M Kool, Marcel Neurooncol Adv Basic and Translational Investigations BACKGROUND: Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients. However, the problem is that tumors frequently acquire resistance to the treatment. To understand the underlying resistance mechanisms and to find ways to overcome the resistance, preclinical models that became resistant to SMO inhibition are needed. METHODS: To induce SMO inhibitor resistant tumors, we have treated a patient-derived xenograft (PDX) model of SHH medulloblastoma, sensitive to SMO inhibition, with 20 mg/kg Sonidegib using an intermitted treatment schedule. Vehicle-treated and resistant models were subjected to whole-genome and RNA sequencing for molecular characterization and target engagement. In vitro drug screens (76 drugs) were performed using Sonidegib-sensitive and -resistant lines to find other drugs to target the resistant lines. One of the top hits was then validated in vivo. RESULTS: Nine independent Sonidegib-resistant PDX lines were generated. Molecular characterization of the resistant models showed that eight models developed missense mutations in SMO and one gained an inactivating point mutation in MEGF8, which acts downstream of SMO as a repressor in the SHH pathway. The in vitro drug screen with Sonidegib-sensitive and -resistant lines identified good efficacy for Selinexor in the resistant line. Indeed, in vivo treatment with Selinexor revealed that it is more effective in resistant than in sensitive models. CONCLUSIONS: We report the first human SMO inhibitor resistant medulloblastoma PDX models, which can be used for further preclinical experiments to develop the best strategies to overcome the resistance to SMO inhibitors in patients. Oxford University Press 2022-03-13 /pmc/articles/PMC9034118/ /pubmed/35475274 http://dx.doi.org/10.1093/noajnl/vdac026 Text en © The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Basic and Translational Investigations
Krausert, Sonja
Brabetz, Sebastian
Mack, Norman L
Schmitt-Hoffner, Felix
Schwalm, Benjamin
Peterziel, Heike
Mangang, Aileen
Holland-Letz, Tim
Sieber, Laura
Korshunov, Andrey
Oehme, Ina
Jäger, Natalie
Witt, Olaf
Pfister, Stefan M
Kool, Marcel
Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma
title Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma
title_full Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma
title_fullStr Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma
title_full_unstemmed Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma
title_short Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma
title_sort predictive modeling of resistance to smo inhibition in a patient-derived orthotopic xenograft model of shh medulloblastoma
topic Basic and Translational Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034118/
https://www.ncbi.nlm.nih.gov/pubmed/35475274
http://dx.doi.org/10.1093/noajnl/vdac026
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