Combinatory EHMT and PARP inhibition induces an interferon response and a CD8 T cell-dependent tumor regression in PARP inhibitor-resistant models

  • bioRxiv. 2023 Feb 23:2023.02.23.529773. doi: 10.1101/2023.02.23.529773.
Lily L Nguyen  1 ,  Zachary L Watson  2 ,  Raquel Ortega  1  2 ,  Elizabeth R Woodruff  2 ,  Kimberly R Jordan  3 ,  Ritsuko Iwanaga  2 ,  Tomomi M Yamamoto  2 ,  Courtney A Bailey  2 ,  Abigail D Jeong  1 ,  Saketh R Guntupalli  4 ,  Kian Behbakht  4 ,  Veronica Gbaja  5 ,  Nausica Arnoult  1 ,  Edward B Chuong  1 ,  Benjamin G Bitler  2
Affiliations
  • 1. Molecular Cellular Developmental Biology, The University of Colorado Boulder, Boulder, CO 80309, USA.
  • 2. Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, 80045.
  • 3. Department of Immunology and Microbiology, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 4. Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 5. Epizyme/Ipsen Company, Cambridge, MA.
PMID: 36865165 DOI: 10.1101/2023.02.23.529773
Abstract

Euchromatic histone lysine methyltransferases 1 and 2 (EHMT1/2), which catalyze demethylation of histone H3 lysine 9 (H3K9me2), contribute to tumorigenesis and therapy resistance through unknown mechanisms of action. In ovarian Cancer, EHMT1/2 and H3K9me2 are directly linked to acquired resistance to poly-ADP-ribose polymerase (PARP) inhibitors and are correlated with poor clinical outcomes. Using a combination of experimental and bioinformatic analyses in several PARP Inhibitor resistant ovarian Cancer models, we demonstrate that combinatory inhibition of EHMT and PARP is effective in treating PARP Inhibitor resistant ovarian cancers. Our in vitro studies show that combinatory therapy reactivates transposable elements, increases immunostimulatory dsRNA formation, and elicits several immune signaling pathways. Our in vivo studies show that both single inhibition of EHMT and combinatory inhibition of EHMT and PARP reduces tumor burden, and that this reduction is dependent on CD8 T cells. Together, our results uncover a direct mechanism by which EHMT inhibition helps to overcome PARP Inhibitor resistance and shows how an epigenetic therapy can be used to enhance anti-tumor immunity and address therapy resistance.

Products