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

Gaia Bianco1, Mairene Coto-Llerena1,2, John Gallon1

  • 1Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.

Communications Biology
|April 20, 2022
PubMed

Insights

Synthetic lethality between GATA3 and MDM2 offers a new therapeutic strategy for estrogen receptor-positive breast cancer. Targeting MDM2 shows promise for patients with GATA3 mutations, improving treatment outcomes.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Synthetic lethal interactions are a validated cancer treatment strategy.
  • GATA3 mutations are common in ER-positive breast cancer, linked to poor prognosis and resistance to hormonal therapy.
  • GATA3 is currently not a druggable target.

Purpose of the Study:

  • To identify synthetic lethal partners for GATA3 in ER-positive breast cancer.
  • To evaluate MDM2 as a potential therapeutic target in GATA3-deficient breast cancer models.

Main Methods:

  • Utilized in vitro, in vivo, and patient-derived organoid/xenograft (PDO/PDX) models of GATA3-deficient ER-positive breast cancer.
  • Assessed the impact of GATA3 and MDM2 inactivation, including pharmacological MDM2 inhibition.
  • Investigated the role of p53 and the PI3K/Akt/mTOR pathway in the synthetic lethality.

Main Results:

  • Demonstrated synthetic lethality between GATA3 and MDM2 in ER-positive breast cancer.
  • MDM2 depletion or inhibition significantly reduced tumor growth in GATA3-deficient models.
  • The synthetic lethal effect is dependent on p53 and involves the PI3K/Akt/mTOR pathway.

Conclusions:

  • MDM2 is a viable therapeutic target for ER-positive breast cancers with GATA3 mutations.
  • MDM2 inhibitors could be rapidly translated into clinical trials for this patient population.

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