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

• DOI: 10.1038/s42003-022-03296-x
• Publication Date: 2022-04-19T10:03:39Z
• Authors: Gaia Bianco; Mairene Coto-Llerena; John Gallon; Venkatesh Kancherla; Stephanie Taha-Me...; Mattia Marinucci; Martina Konantz; Sumana Srivatsa; Hesam Montazeri; Federica Panebianco; Vijaya G. Tirunagaru; Marta De Menna; Viola Paradiso; Caner Ercan; Ahmed Dahmani; Elodie Montaudon; Niko Beerenwinkel; Marianna Kruithof...; Luigi M. Terracciano; Claudia Lengerke; Rinath M. Jeselsohn; Robert C. Doebele; François-Clément ...; Elisabetta Marangoni; Charlotte K. Y. Ng; Salvatore Piscuoglio
• Keywords: 0301 basic medicine; 0303 health sciences; QH301-705.5; 610 Medicine & health; Antineoplastic Agents; Breast Neoplasms; Proto-Oncogene Proteins c-mdm2; GATA3 Transcription Factor; Article; 3. Good health; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Receptors, Estrogen; Humans; Female; Biology (General)

AbstractSynthetic 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 yet targetable. Here we show thatGATA3andMDM2are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 significantly impaired tumor growth inGATA3-deficient models in vitro, in vivo and in patient-derived organoids/xenograft (PDOs/PDX) harboringGATA3somatic mutations. The synthetic lethality requires p53 and acts via the PI3K/Akt/mTOR pathway. Our results present MDM2 as a 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.