Synthetic lethal interactions, where the simultaneous but not individual inactivation of two genes is lethal to the cell, have been successfully exploited to treat cancer. GATA3 is frequently mutated in estrogen receptor (ER)-positive breast cancers and its deficiency defines a subset of patients with poor response to hormonal therapy. However, GATA3 is not targetable. Here we show that GATA3 and MDM2 are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 induce apoptosis in GATA3-deficient models in vitro and in vivo. 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-deficient breast cancer patients. With MDM2 inhibitors widely available, our findings can be rapidly translated into clinical trials to evaluate in-patient efficacy.
Statement of significance
GATA3 mutations are common in ER-positive breast cancers yet are not targetable. Our findings describe pharmacological inhibition of MDM2 as a novel approach to target GATA3 deficiency, providing a molecularly guided treatment for this patient subclass associated with a worse prognosis and relapse.