A 'weak spot' discovered that potentially makes multi-drug r
FBXW7 mutations are among the most frequent in cancer. This study reveals that while FBXW7 deficiency renders cells resistant to most chemotherapies, it also leads to mitochondrial stress and renders cancer cells vulnerable to drugs activating the Integrated Stress Response (ISR). FBXW7 deficiency leads to a broad multidrug-resistant (MDR) phenotype. Loss of FBXW7 increases mitochondrial factors expression, yet functional analyses reveal that these mitochondria are under stress. Genetically or chemically targeting mitochondria is toxic for FBXW7 deficient cells.
Despite the broad MDR associated with FBXW7 deficiency, FBXW7 loss sensitizes cancer cells to drugs activating the ISR through GCN2. Several kinase inhibitors used in the clinic exert toxicity through activation of a GCN2-dependent ISR.

Source: https://www.embopress.org/doi/full/10.15252/emmm.202215855