Previously, Selivanova and colleaques have shown that the inhibition of thioredoxin reducatase (TrxR), important anti-oxidant enzyme often upregulated in cancers, is synthetic lethal with p53 activation and that ROS-activated JNK mediates this effect.46 Here, using two small-molecule inhibitors of the 20S proteasome, we demonstrated that the activation of JNK and inhibition of 20S proteasome confers synthetic lethality in cancer cells. Here, MAPK8 is linked to cancer.