2026-07-23T23:02:09Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/176932025-03-20T10:48:40Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Sanchez-Burgos, Laura author Navarro-González, Belén author García-Martín, Santiago author Sirozh, Oleksandra author Mota-Pino, Jorge author Fueyo-Marcos, Elena author Tejero, Héctor author Antón, Marta Elena author Murga, Matilde author Al-Shahrour, Fatima author Fernandez-Capetillo, Oscar author 2022-09-07 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. EMBO Mol Med . 2022 ;14(9):e15855 10.15252/emmm.202215855 1757-4684 EMBO molecular medicine 35861150 http://hdl.handle.net/20.500.12105/17693 Activation of the integrated stress response is a vulnerability for multidrug-resistant FBXW7-deficient cells.