GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers

SummarySynthetic lethal interactions, where the simultaneous but not individual inactivation of two genes is lethal to the cell, have been successfully exploited to treat cancer.GATA3is frequently mutated in estrogen receptor (ER)-positive breast cancers and its deficiency defines a subset of patients with poor response to hormonal therapy and poor prognosis. However, GATA3 is not targetable. Here we show thatGATA3andMDM2are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 induce apoptosis inGATA3-deficient modelsin vitro, in vivoand in patient-derived organoids (PDOs) harboringGATA3somatic mutation. The synthetic lethality requires p53 and acts via the PI3K/Akt/mTOR pathway. Our results present MDM2 as a novel therapeutic target in the substantial cohort of ER-positive,GATA3-mutant breast cancer patients. With MDM2 inhibitors widely available, our findings can be rapidly translated into clinical trials to evaluate in-patient efficacy.