ERN1 and cancer: To examine whether G6374 could be leveraged against cancer cells that possess either enzymatic or nonenzymatic IRE1 dependency, we tested the effect of the compound as compared to Dox-induced shIRE1 knockdown on IRE1 protein levels (Supplementary Fig. 6a–e) and on proliferation using an automated live-cell imaging instrument (Fig. 6a–e).