TY  - JOUR
AU  - Schwarz, Franziska Maria
AU  - Klotz, Daniel Martin
AU  - Yang, Ruming
AU  - Brux, Melanie
AU  - Buchholz, Frank
AU  - Harb, Hani
AU  - Link, Theresa
AU  - Wimberger, Pauline
AU  - Theis, Mirko
AU  - Kuhlmann, Jan Dominik
TI  - Methylstat sensitizes ovarian cancer cells to PARP-inhibition by targeting the histone demethylases JMJD1B/C.
JO  - Cancer gene therapy
VL  - 32
IS  - 3
SN  - 0929-1903
CY  - New York, NY
PB  - Nature Publ. Group
M1  - DKFZ-2025-00306
SP  - 286-296
PY  - 2025
N1  - 2025 Mar;32(3):286-296
AB  - PARP-inhibitors (PARPi) are an integral part of ovarian cancer treatment. However, overcoming acquired PARPi resistance or increasing the benefit of PARPi in patients without homologous recombination deficiency (HRD) remains an unmet clinical need. We sought to identify genetic modulators of PARPi response, guiding pharmacological PARPi sensitization. CRISPR-Cas9 mediated loss-of-function screen with a focused sgRNA library revealed that DNA-demethylases JMJD1B/JMJD1C, targetable by the small inhibitor methylstat, promote PARPi resistance. Methylstat synergistically interacted with olaparib, and (re-)sensitized ovarian cancer cells to PARPi treatment, surpassing the efficacy of common demethylase inhibitors. Genetic knockout of JMJD1B and/or JMJD1C phenocopied the effect of methylstat in an additive manner. Validation studies revealed methylstat to be a universal PARPi-sensitizing drug, effective, regardless of PARPi resistance status or BRCA1 mutational background. Methylstat modulated clonal cancer dynamics by mitigating positive selection of PARPi-resistant or BRCA1-proficient cells under olaparib treatment. Using a model of PARPi-induced cellular toxicity, we showed that methylstat impairs cellular DNA repair, indicated by an increased susceptibility of ovarian cancer cells to olaparib-induced DNA double strand breaks after methylstat exposure. This study proposes the histone demethylase inhibitor methylstat as an epigenetic drug for overcoming PARPi-resistance or for increasing efficacy of PARPi beyond HRD in ovarian cancer patients.
LB  - PUB:(DE-HGF)16
C6  - pmid:39915607
DO  - DOI:10.1038/s41417-025-00874-z
UR  - https://inrepo02.dkfz.de/record/298596
ER  -