EHMT1/2 Inhibition Promotes Regression of Therapy-Resistant Ovarian Cancer Tumors in a CD8 T-cell–Dependent Manner
Year: 2024
Type: article
Abstract: 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.
Source: Molecular Cancer Research
Authors: Lily L. Nguyen, Zachary L. Watson, Raquel Ortega, Elizabeth R. Woodruff, Kimberly R. Jordan, Ritsuko Iwanaga, Tomomi M. Yamamoto, Courtney A. Bailey, Francis To, Shujian Lin, Fabian R. Villagomez, Abigail D. Jeong, Saketh R. Guntupalli, Kian Behbakht, Veronica Gibaja, Nausica Arnoult, Edward B. Chuong, Benjamin G. Bitler
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
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, National Cancer Institute, National Institute of General Medical Sciences, All of Us Research Program
Awards: Elucidating the role of Chromobox 2 in promoting ovarian cancer progression, G111418884, G1214036451, G1565180698, G194370714, G2419980018, Transposon-mediated rewiring of gene regulatory networks, G310896420, G3278220073, Targeting Wnt signaling to overcome PARP inhibitor resistance in ovarian cancer, G518459632, G5550786099, G5920139415, G6867399807, G8330263542, G8483720623, G9000308714, Targeting Wnt signaling in therapy-resistant ovarian cancer, University of Colorado Cancer Center Support Grant, Deciphering the function of the APE2 nuclease during repair by alternative end-joining and its role in HR-deficient cells, G9001225491
OpenAlex ID: W4401542526