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Highlights d Synthetic lethal and resistance interactions with BET inhibitors in TNBC d Multiple independent unbiased screens identify the same genes and pathways d CDK4/6 inhibitors and paclitaxel have top synergies with BET bromodomain inhibitors d Deletion of SNF/SWI complex components leads to BET inhibitor resistance

Highlights d Most cancer cell lines are largely insensitive to GSH depletion d Deubiquitinases (DUBs) protect cancer cells upon inhibition of GSH synthesis d Inhibition of DUBs and GSH synthesis causes ER and proteotoxic stress and cell death d Combined targeting of DUBs and GSH blocks tumor growth

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