Ceramides induce ISR activation and sensitize cells to Bcl-2 inhibition. The accumulation of proapoptotic sphingolipids, such as ceramide, in response to SPHK inhibition is sensed by the eIF2a kinase PKR. PKR activation culminates in an apoptotic ISR mediated by master transcription factor ATF4. ATF4 promotes Bcl-2 dependency by the transcriptional upregulation of Noxa and the subsequent binding to and inactivation of Mcl-1.