Targeting oxidative phosphorylation with lixumistat overcomes PARP inhibitor resistance in ovarian cancer
- 1Department of Biomedical Science, The Graduate School, CHA University, Seongnam-si, Republic of Korea
- 2Hematology and Oncology, CHA Bundang Medical Center, CHA University, Seongnam-si, Republic of Korea
Abstract
Ovarian cancer remains the leading cause of gynecologic cancer mortality, yet nearly half of BRCA1/2-mutated ovarian cancer patients eventually develop resistance to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we investigated whether lixumistat, a novel oxidative phosphorylation (OXPHOS) inhibitor, could overcome PARP inhibitor resistance in preclinical BRCA1/2-mutated ovarian cancer models. Long-term olaparib exposure generated olaparib-resistant BRCA-mutated ovarian cancer cell lines and patient-derived tumor xenograft (PDTX) models. Olaparib-resistant cells exhibited elevated OXPHOS activity. Lixumistat, when combined with olaparib, demonstrated synergistic antitumor effects in both olaparib-sensitive and -resistant cell lines and PDTX models. Switching from olaparib monotherapy to combination markedly suppressed tumor growth in partially resistant and acquired-resistant PDTX models. These results suggest that early integration of lixumistat could enhance efficacy and delay PARP inhibitor resistance. Mechanistically, lixumistat restores PARP inhibitor sensitivity by inhibiting the OXPHOS–NAD⁺-poly(ADP)-ribosylation (PARylation) axis, which reduces NAD⁺ availability and subsequent PARylation. Exogenous NAD⁺ reversed these effects. Additionally, lixumistat downregulated the SNAIL-mediated IL6-phosphorylated STAT3 and phosphorylated retinoblastoma pathway, impairing cell-cycle progression and further enhancing PARP inhibitor efficacy. Together, these findings identify a novel OXPHOS-associated mechanism underlying PARP inhibitor resistance and establish lixumistat as a promising combinatorial strategy to potentiate PARP inhibitors in both PARP inhibitor-naive and -resistant ovarian cancer.
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BibTeX
@article{hong2026targeting,
title = {{Targeting oxidative phosphorylation with lixumistat overcomes PARP inhibitor resistance in ovarian cancer}},
author = {Sa Deok Hong and Nar Bahadur Katuwal and Mithun Ghosh and Seong Min Park and Ju Hyun Kim and Seul-Gi Kim and Min Sil Kang and Yong Wha Moon},
journal = {Cell Death \& Disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09140-y},
url = {https://doi.org/10.1038/s41419-026-09140-y},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting oxidative phosphorylation with lixumistat overcomes PARP inhibitor resistance in ovarian cancer
AU - Sa Deok Hong
AU - Nar Bahadur Katuwal
AU - Mithun Ghosh
AU - Seong Min Park
AU - Ju Hyun Kim
AU - Seul-Gi Kim
AU - Min Sil Kang
AU - Yong Wha Moon
PY - 2026
DA - 2026/08/07
JO - Cell Death & Disease
DO - 10.1038/s41419-026-09140-y
UR - https://doi.org/10.1038/s41419-026-09140-y
AB - Ovarian cancer remains the leading cause of gynecologic cancer mortality, yet nearly half of BRCA1/2-mutated ovarian cancer patients eventually develop resistance to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we investigated whether lixumistat, a novel oxidative phosphorylation (OXPHOS) inhibitor, could overcome PARP inhibitor resistance in preclinical BRCA1/2-mutated ovarian cancer models. Long-term olaparib exposure generated olaparib-resistant BRCA-mutated ovarian cancer cell lines and patient-derived tumor xenograft (PDTX) models. Olaparib-resistant cells exhibited elevated OXPHOS activity. Lixumistat, when combined with olaparib, demonstrated synergistic antitumor effects in both olaparib-sensitive and -resistant cell lines and PDTX models. Switching from olaparib monotherapy to combination markedly suppressed tumor growth in partially resistant and acquired-resistant PDTX models. These results suggest that early integration of lixumistat could enhance efficacy and delay PARP inhibitor resistance. Mechanistically, lixumistat restores PARP inhibitor sensitivity by inhibiting the OXPHOS–NAD⁺-poly(ADP)-ribosylation (PARylation) axis, which reduces NAD⁺ availability and subsequent PARylation. Exogenous NAD⁺ reversed these effects. Additionally, lixumistat downregulated the SNAIL-mediated IL6-phosphorylated STAT3 and phosphorylated retinoblastoma pathway, impairing cell-cycle progression and further enhancing PARP inhibitor efficacy. Together, these findings identify a novel OXPHOS-associated mechanism underlying PARP inhibitor resistance and establish lixumistat as a promising combinatorial strategy to potentiate PARP inhibitors in both PARP inhibitor-naive and -resistant ovarian cancer.
SN - 2041-4889
ER -