ArticleEMBO molecular medicine2022
Activation of the integrated stress response is a vulnerability for multidrug-resistant FBXW7-deficient cells.
Article in EMBO molecular medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 26 citations in OpenAlex.
- FBXW7 Gene Mutation and Expression in Colorectal Cancer (CRC): A Systematic Review from Molecular Mechanisms to Clinical Translation.International journal of molecular sciences · 2025Pooled it
- Genomic insights into the tunicamycin-induced endoplasmic reticulum stress response in peripheral blood mononuclear cells: A comprehensive RNA sequencing analysis.Biochemistry and biophysics reports · 2026Article
- Elevated GCN2 levels in cancer cells confer protection from mitotic stress and faster cell movement.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- Class IIa HDACs forced degradation allows resensitization of oxaliplatin-resistant FBXW7-mutated colorectal cancer.Molecular oncology · 2026Article
- SETD8 inhibition targets cancer cells with increased rates of ribosome biogenesis.Cell death & disease · 2024Article
- In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAFCell reports. Medicine · 2024Article
- Sublethal engagement of apoptotic pathways in residual cancer.Trends in cell biology · 2024Review
- Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity.Circulation research · 2024Article
- Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7.Molecular oncology · 2024Article
- Regulation of p53 by the mitotic surveillance/stopwatch pathway: implications in neurodevelopment and cancer.Frontiers in cell and developmental biology · 2024Review
- Mitoribosomal synthetic lethality overcomes multidrug resistance in MYC-driven neuroblastoma.Cell death & disease · 2023Article
- Revolutionizing DNA repair research and cancer therapy with CRISPR-Cas screens.Nature reviews. Molecular cell biology · 2023Review
- Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC-driven lymphoma.EMBO molecular medicine · 2023Article
- Lights and Shadows on the Cancer Multi-Target Inhibitor Rigosertib (ON-01910.Na).Pharmaceutics · 2023Review
- FBXW7 attenuates tumor drug resistance and enhances the efficacy of immunotherapy.Frontiers in oncology · 2023Review
- New mechanisms of multidrug resistance: an introduction to theCancer drug resistance (Alhambra, Calif.) · 2023Article
- MYC and therapy resistance in cancer: risks and opportunities.Molecular oncology · 2022Review
- Activation of the integrated stress response is a vulnerability for multidrug-resistant FBXW7-deficient cells.EMBO molecular medicine · 2022Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.