EHMT1/2 Inhibition Promotes Regression of Therapy-Resistant Ovarian Cancer Tumors in a CD8 T-cell–Dependent Manner
Poly ADP-ribose polymerase inhibitors (PARPi) are first-line maintenance therapy for ovarian cancer and an alternative therapy for several other cancer types. However, PARPi-resistance is rising, and there is currently an unmet need to combat PARPi-resistant tumors. Here, we created an immunocompetent, PARPi-resistant mouse model to test the efficacy of combinatory PARPi and euchromatic histone methyltransferase 1/2 inhibitor (EHMTi) in the treatment of PARPi-resistant ovarian cancer. We discovered that inhibition of EHMT1/2 resensitizes cells to PARPi. Markedly, we show that single EHMTi and combinatory EHMTi/PARPi significantly reduced PARPi-resistant tumor burden and that this reduction is partially dependent on CD8 T cells. Altogether, our results show a low-toxicity drug that effectively treats PARPi-resistant ovarian cancer in an immune-dependent manner, supporting its entry into clinical development and potential incorporation of immunotherapy. Implications: Targeting the epigenome of therapy-resistant ovarian cancer induces an antitumor response mediated in part through an antitumor immune response.
Authors
- Nausica Arnoult (ORCID: https://orcid.org/0000-0003-2633-0270)
- Courtney A. Bailey (ORCID: https://orcid.org/0000-0003-0176-7601)
- Tomomi M. Yamamoto (ORCID: https://orcid.org/0000-0002-6666-5406)
- Benjamin G. Bitler (ORCID: https://orcid.org/0000-0002-5809-5271)
- Francis To
- Zachary L. Watson (ORCID: https://orcid.org/0000-0001-9425-1449)
- Raquel Ortega (ORCID: https://orcid.org/0000-0003-1954-0704)
- Kimberly Rae Jordan (ORCID: https://orcid.org/0000-0001-8380-7157)
- Abigail D. Jeong (ORCID: https://orcid.org/0009-0000-1240-5898)
- Edward B. Chuong (ORCID: https://orcid.org/0000-0002-5392-937X)
- Kian Behbakht (ORCID: https://orcid.org/0000-0003-4793-9958)
- Saketh R. Guntupalli (ORCID: https://orcid.org/0000-0003-2570-6635)
- Lily L. Nguyen (ORCID: https://orcid.org/0000-0003-4425-2536)
- Ritsuko Iwanaga (ORCID: https://orcid.org/0009-0008-1142-4753)
- Shujian Lin (ORCID: https://orcid.org/0009-0004-0386-6480)
- Elizabeth R. Woodruff (ORCID: https://orcid.org/0000-0003-0237-7453)
- Veronica Gibaja (ORCID: https://orcid.org/0009-0008-7785-9362)
- Fabian R. Villagómez (ORCID: https://orcid.org/0000-0002-4510-1329)
Institutions
- University of Colorado Boulder (US)
- Epizyme (United States) (US)
- Abeona Therapeutics (United States) (US)
- Ipsen (United States) (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Molecular Cancer Research
- Published
- 2024-08-13
- DOI
- https://doi.org/10.1158/1541-7786.mcr-24-0067
- Citations
- 7
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- U.S. Department of Defense
- American Cancer Society
- Alfred P. Sloan Foundation
- Glenn Foundation for Medical Research
- Boettcher Foundation
- Ovarian Cancer Research Alliance
- National Institutes of Health
- Cancer Center, University of Colorado