EHMT1/2 inhibition promotes regression of therapy-resistant ovarian cancer tumors in a CD8 T cell-dependent manner.

Autor:	Nguyen LL; University of Colorado Denver, Aurora, CO, United States., Watson ZL; University of Colorado Anschutz Medical Campus, Aurora, CO, United States., Ortega R; University of Colorado Boulder, Boulder, United States., Woodruff ER; University of Colorado Anschutz Medical Campus, Aurora, CO, United States., Jordan KR; University of Colorado Anschutz Medical Campus, Aurora, CO, United States., Iwanaga R; University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States., Yamamoto TM; University of Colorado Denver, Aurora, CO, United States., Bailey CA; University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States., To F; University of Colorado Anschutz Medical Campus, Aurora, CO, United States., Lin S; University of Colorado Denver, Aurora, CO, United States., Villagomez FR; University of Colorado Anschutz Medical Campus, Aurora, United States., Jeong AD; University of Colorado Boulder, Boulder, CO, United States., Guntupalli SR; University of Colorado Anschutz Medical Campus, Aurora, CO, United States., Behbakht K; University of Colorado Anschutz Medical Campus, Aurora, CO, United States., Gibaja V; Redona Therapeutics, Watertown, MA, United States., Arnoult N; University of Colorado Boulder, United States., Chuong EB; The University of Colorado Boulder, United States., Bitler BG; University of Colorado Denver, Aurora, CO, United States.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2024 Aug 13. Date of Electronic Publication: 2024 Aug 13.
DOI:	10.1158/1541-7786.MCR-24-0067
Abstrakt:	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 anti-tumor response mediated in part through an anti-tumor immune response.
Databáze:	MEDLINE
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