Abstract 3984: GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers

Abstract

Abstract Introduction: GATA3 is critical for the development of the mammary gland and the loss of its expression alters the estrogen receptor (ER) transcriptional program. Approximately 70%-80% of all breast cancers are ER-positive and 15-18% of them harbor GATA3 somatic mutations. Clinically, GATA3 loss defines a subset of patients with poor response to hormonal therapy and poor prognosis. As a transcription factor, however, GATA3 is not pharmacologically targetable. Synthetic lethality refers to the interaction between genetic events in two genes whereby the inactivation of either gene results in a viable phenotype, while their combined inactivation is lethal. This approach enables the indirect targeting of undruggable genes by disrupting their genetic interactors. In this study we sought to define Synthetic lethal partners for GATA3 and explore possible therapeutic targets Methods: Putative synthetic lethal partners for GATA3 were identified using the recently developed SLIdR (Synthetic Lethal Identification in R) algorithm. The synthetic lethal interaction and the anti-tumoral effect of putative partner was evaluated via genetic silencing or pharmacological inhibition using in-vitro, ex-vivo and in-vivo models. Putative mechanisms of action were investigate using RNA sequencing and confirmed using molecular biology technologies. Results: We identify MDM2 as synthetically lethal partner of GATA3 in ER-positive breast cancer. Using a siRNA approach, we first validated in-silico data by confirming that silencing MDM2 significantly reduces cell proliferation of GATA3-mutant in-vitro models by inducing apoptosis. Pharmacological inhibition of MDM2 using three different compounds (RG7388-idasanutlin, RAIN-32 and MI-733) significantly impaired tumor growth in GATA3-deficient models in vitro, in vivo and in patient-derived organoid/xenograft (PDO/PDX) harboring GATA3 somatic mutation. Additionally, we showed that the synthetic lethality between GATA3 and MDM2 is p53-dependent and acts at least partially via the PI3K/Akt/mTOR pathway. This suggests that GATA3 loss-of-function (via genetic alterations or other mechanisms) activates the PI3K/Akt/mTOR pathway and leads to resistance to apoptosis. Conclusion: 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. Citation Format: Mattia Marinucci, Gaia Bianco, Mairene Coto-Llierena, John Gallon, Venkatesh Kancherla, Federica Panebianco, Stephanie Taha-Mehlitz, Sumana Srivatsa, Niko Beerenwinkel, Hesam Montazeri, Vijaya Tirunagaru, Marta De Menna, Caner Ercan, Ahmed Dahmani, Elodie Montaudon, Marianna Kruithof-de Julio, Luigi M. Terracciano, Rinath M. Jeselsohn, Robert C. Doebele, François-Clément Bidard, Elisabetta Marangoni, Charlotte K. Y. Ng, Salvatore Piscuoglio. GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3984.