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EHMT1/2 Inhibition Promotes Regression of Therapy-Resistant Ovarian Cancer Tumors in a CD8 T-cell-Dependent Manner

Lily L Nguyen1,2, Zachary L Watson2, Raquel Ortega1,2

  • 1Molecular Cellular Developmental Biology, The University of Colorado Boulder, Boulder, Colorado.

Molecular Cancer Research : MCR
|August 13, 2024
PubMed

Insights

Poly ADP-ribose polymerase inhibitors (PARPi) combat ovarian cancer, but resistance is increasing. Combining PARPi with euchromatic histone methyltransferase 1/2 inhibitors (EHMTi) effectively treats PARPi-resistant tumors, partly via CD8 T cells.

Area of Science:

  • Oncology
  • Epigenetics
  • Immunotherapy

Background:

  • Poly ADP-ribose polymerase inhibitors (PARPi) are crucial for ovarian cancer treatment.
  • Rising resistance to PARPi necessitates novel therapeutic strategies.
  • There is an unmet need for effective treatments against PARPi-resistant tumors.

Purpose of the Study:

  • To evaluate the efficacy of combining PARPi with euchromatic histone methyltransferase 1/2 inhibitors (EHMTi) in PARPi-resistant ovarian cancer.
  • To investigate the role of the immune system in mediating treatment response.

Main Methods:

  • Development of an immunocompetent, PARPi-resistant ovarian cancer mouse model.
  • Administration of single EHMTi and combination EHMTi/PARPi therapies.
  • Assessment of tumor burden reduction and immune cell involvement (CD8 T cells).

Main Results:

  • Inhibition of EHMT1/2 resensitizes cancer cells to PARPi.
  • Both single EHMTi and combined EHMTi/PARPi treatments significantly reduced tumor burden.
  • The observed tumor reduction was partially dependent on CD8 T cells.

Conclusions:

  • Combining EHMTi with PARPi is a promising, low-toxicity approach for treating PARPi-resistant ovarian cancer.
  • The treatment elicits an immune-dependent antitumor response, suggesting potential for immunotherapy integration.
  • This strategy supports clinical development for therapy-resistant ovarian cancer.

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