Home » Abstracts » Human Health Proteomics » Thermal proteome profiling unveils the polypharmacology of mebendazole and identifies novel targetable vulnerabilities in glioblastoma

Thermal proteome profiling unveils the polypharmacology of mebendazole and identifies novel targetable vulnerabilities in glioblastoma

Human Health Proteomics

Abstract #142 Posted on25 March 202512 May 2025 12 May 2025 13h11

Author(s)

Baptiste Mouysset | Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM) | 27 BD LEI ROURE, 13273, Marseille, France
Marc-Antoine Gerault | Marseille Proteomics Platform, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Aix-Marseille Université | 27 BD LEI ROURE, 13273, Marseille, France
Jérémy Ariey-Bonnet | Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS)Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), | 27 BD LEI ROURE, 13273, Marseille, France
Raphael Berges | Aix Marseille Université, CNRS, UMR 7051, INP, Inst Neurophysiopathol | Faculté des Sciences Médicales et Paramédicales 27 Boulevard Jean Moulin, 13005, Marseille, France
Kevin Muller | Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM) | 27 BD LEI ROURE, 13273, Marseille, France
Marie-Pierre Montero | Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM) | 27 BD LEI ROURE, 13273, Marseille, France
Nicolas André | Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM) and Pediatric Oncology and Hematology Department, Hôpital pour Enfant de La Timone, AP-HM | 27 BD LEI ROURE, 13273, Marseille, France
Manon Carré | Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM) | 27 BD LEI ROURE, 13273, Marseille, France
Stéphane Audebert | Marseille Proteomics Platform, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Aix-Marseille Université | 27 BD LEI ROURE, 13273, Marseille, France
LUC CAMOIN (Presenting Author) | Marseille Proteomics Platform, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Aix-Marseille Université | 27 BD LEI ROURE, 13273, Marseille, France
Marion Le Grand | Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM) | 27 BD LEI ROURE, 13273, Marseille, France
Eddy Pasquier | Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), | 27 BD LEI ROURE, 13273, Marseille, France

Abstract

Drug repurposing, which consists in using already approved drugs in new indications, is an effective strategy to rapidly develop new treatments against refractory cancers.

We previously highlighted the role of MAPK14 in the anti-cancer effects of mebendazole, a benzimidazole-based anti-helminthic agent effective against glioblastoma. In this study, our drug screening data revealed that benzimidazoles are more cytotoxic to brain cancer cell lines than selective MAPK14 inhibitors, suggesting that mebendazole has additional targets implicated in its antitumour effects, which remain to be identified.

To unveil its polypharmacology (= simultaneous interaction of a molecule with multiple targets), we developed an innovative chemo-proteomics strategy called DIA-TPP (Data Independent Acquisition – Thermal Proteome Profiling) to map the interactome of mebendazole in glioblastoma cells and fully characterize its mechanism of action.

Our results confirmed that mebendazole acts by engaging MAPK14 and also the PRMT5-WDR77 methylosome complex. Our functional and pharmacological studies showed that all three targets play a key role in tumour spheroid growth and response to mebendazole treatment.
Altogether, our study shows that deciphering the polypharmacology of existing drugs has the potential to reveal exploitable vulnerabilities in refractory cancers.

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Drug repurposing, which consists in using already approved drugs in new indications, is an effective strategy to rapidly develop new treatments against refractory cancers.

We previously highlighted the role of MAPK14 in the anti-cancer effects of mebendazole, a benzimidazole-based anti-helminthic agent effective against glioblastoma. In this study, our drug screening data revealed that benzimidazoles are more cytotoxic to brain cancer cell lines than selective MAPK14 inhibitors, suggesting that mebendazole has additional targets implicated in its antitumour effects, which remain to be identified.

To unveil its polypharmacology (= simultaneous interaction of a molecule with multiple targets), we developed an innovative chemo-proteomics strategy called DIA-TPP (Data Independent Acquisition – Thermal Proteome Profiling) to map the interactome of mebendazole in glioblastoma cells and fully characterize its mechanism of action.

Our results confirmed that mebendazole acts by engaging MAPK14 and also the PRMT5-WDR77 methylosome complex. Our functional and pharmacological studies showed that all three targets play a key role in tumour spheroid growth and response to mebendazole treatment.
Altogether, our study shows that deciphering the polypharmacology of existing drugs has the potential to reveal exploitable vulnerabilities in refractory cancers.

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