Bianco, Gaia; Coto-Llerena, Mairene; Gallon, John; Kancherla, Venkatesh; Taha-Mehlitz, Stephanie; Marinucci, Mattia; Konantz, Martina; Srivatsa, Sumana; Montazeri, Hesam; Panebianco, Federica; Tirunagaru, Vijaya G; De Menna, Marta; Paradiso, Viola; Ercan, Caner; Dahmani, Ahmed; Montaudon, Elodie; Beerenwinkel, Niko; Kruithof-de Julio, Marianna; Terracciano, Luigi M; Lengerke, Claudia; ... (2022). GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers. Communications biology, 5(1), p. 373. Springer Nature 10.1038/s42003-022-03296-x
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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 and poor prognosis. However, GATA3 is not yet targetable. Here we show that GATA3 and MDM2 are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 significantly impaired tumor growth in GATA3-deficient models in vitro, in vivo and in patient-derived organoids/xenograft (PDOs/PDX) harboring GATA3 somatic 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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie |
UniBE Contributor: |
De Menna, Marta, Ng, Kiu Yan Charlotte |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2399-3642 |
Publisher: |
Springer Nature |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
21 Apr 2022 12:28 |
Last Modified: |
05 Dec 2022 16:19 |
Publisher DOI: |
10.1038/s42003-022-03296-x |
PubMed ID: |
35440675 |
BORIS DOI: |
10.48350/169419 |
URI: |
https://boris.unibe.ch/id/eprint/169419 |
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