Open AccessActivation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7 ‐deficient cells
Author(s) -
SanchezBurgos Laura,
NavarroGonzález Belén,
GarcíaMartín Santiago,
Sirozh Oleksandra,
MotaPino Jorge,
FueyoMarcos Elena,
Tejero Héctor,
Antón Marta Elena,
Murga Matilde,
AlShahrour Fátima,
FernandezCapetillo Oscar
Publication year - 2022
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202215855
Subject(s) - mitochondrion , downregulation and upregulation , integrated stress response , biology , multiple drug resistance , suppressor , mutation , crispr , dna damage , genetics , cancer research , translation (biology) , microbiology and biotechnology , cancer , drug resistance , gene , dna , messenger rna
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.