Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells
Abstract FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome‐wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic ana...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-07-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202215855 |
| _version_ | 1826990694784303104 |
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| author | Laura Sanchez‐Burgos Belén Navarro‐González Santiago García‐Martín Oleksandra Sirozh Jorge Mota‐Pino Elena Fueyo‐Marcos Héctor Tejero Marta Elena Antón Matilde Murga Fátima Al‐Shahrour Oscar Fernandez‐Capetillo |
| author_facet | Laura Sanchez‐Burgos Belén Navarro‐González Santiago García‐Martín Oleksandra Sirozh Jorge Mota‐Pino Elena Fueyo‐Marcos Héctor Tejero Marta Elena Antón Matilde Murga Fátima Al‐Shahrour Oscar Fernandez‐Capetillo |
| author_sort | Laura Sanchez‐Burgos |
| collection | DOAJ |
| description | Abstract FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome‐wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic analyses found an upregulation of mitochondrial factors as a hallmark of FBXW7 deficiency, which has been previously linked to chemotherapy resistance. Despite this increased expression of mitochondrial factors, functional analyses revealed that mitochondria are under stress, and genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7‐deficient cells. Mechanistically, the toxicity of therapies targeting mitochondrial translation such as the antibiotic tigecycline relates to the activation of the integrated stress response (ISR) in a GCN2 kinase‐dependent manner. Furthermore, the discovery of additional drugs that are toxic for FBXW7‐deficient cells showed that all of them unexpectedly activate a GCN2‐dependent ISR regardless of their accepted mechanism of action. Our study reveals that while one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, it renders cells vulnerable to ISR‐activating drugs. |
| first_indexed | 2024-03-07T18:31:43Z |
| format | Article |
| id | doaj.art-256932fb4a3044ed836a66ac7c89974f |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T08:24:22Z |
| publishDate | 2022-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-256932fb4a3044ed836a66ac7c89974f2024-11-03T12:39:39ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-07-0114911810.15252/emmm.202215855Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cellsLaura Sanchez‐Burgos0Belén Navarro‐González1Santiago García‐Martín2Oleksandra Sirozh3Jorge Mota‐Pino4Elena Fueyo‐Marcos5Héctor Tejero6Marta Elena Antón7Matilde Murga8Fátima Al‐Shahrour9Oscar Fernandez‐Capetillo10Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO)Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO)Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO)Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)Abstract FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome‐wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic analyses found an upregulation of mitochondrial factors as a hallmark of FBXW7 deficiency, which has been previously linked to chemotherapy resistance. Despite this increased expression of mitochondrial factors, functional analyses revealed that mitochondria are under stress, and genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7‐deficient cells. Mechanistically, the toxicity of therapies targeting mitochondrial translation such as the antibiotic tigecycline relates to the activation of the integrated stress response (ISR) in a GCN2 kinase‐dependent manner. Furthermore, the discovery of additional drugs that are toxic for FBXW7‐deficient cells showed that all of them unexpectedly activate a GCN2‐dependent ISR regardless of their accepted mechanism of action. Our study reveals that while one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, it renders cells vulnerable to ISR‐activating drugs.https://doi.org/10.15252/emmm.202215855drug resistanceFBXW7GCN2ISRmitochondria |
| spellingShingle | Laura Sanchez‐Burgos Belén Navarro‐González Santiago García‐Martín Oleksandra Sirozh Jorge Mota‐Pino Elena Fueyo‐Marcos Héctor Tejero Marta Elena Antón Matilde Murga Fátima Al‐Shahrour Oscar Fernandez‐Capetillo Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells EMBO Molecular Medicine drug resistance FBXW7 GCN2 ISR mitochondria |
| title | Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells |
| title_full | Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells |
| title_fullStr | Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells |
| title_full_unstemmed | Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells |
| title_short | Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells |
| title_sort | activation of the integrated stress response is a vulnerability for multidrug resistant fbxw7 deficient cells |
| topic | drug resistance FBXW7 GCN2 ISR mitochondria |
| url | https://doi.org/10.15252/emmm.202215855 |
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