Mitotic MTH1 inhibitor karonudib kills epithelial ovarian cancer independent of platinum sensitivity.

Abstract

The prognosis for women with ovarian cancer (OC) is particularly poor if resistance to platinum compounds, the mainstay of standard-of-care therapy, develops. Inhibitors of the Nudix hydrolase MuT Homolog 1 (MTH1) have previously been shown to arrest cancer cells in mitosis, increase 8-oxo-2'-deoxyguanosine (8-oxo-dG) incorporation into DNA, and selectively kill neoplastic cells while sparing normal cells. Here we explored the cytotoxic mechanism of these agents as well as their activity against platinum-resistant OC in vitro and in vivo. Two mitotic MTH1 inhibitors (mMTH1is), TH588 and karonudib, decreased colony formation indistinguishably in platinum-sensitive OC cell lines and their platinum-resistant counterparts in vitro but had limited effects on fallopian tube and immortalized ovarian surface epithelial cells. Treatment with karonudib stalled OC cells in mitosis and caused elevated 8-oxo-dG levels in DNA followed by activation of base excision repair, induction of BAX, and apoptotic cellular demise. This cytotoxicity was blunted by overexpression of the pre-mitotic checkpoint protein CHFR, which inhibits other anti-mitotics, or treatment with the antioxidant N-acetylcysteine, which diminishes nuclear 8-oxo-dG staining, suggesting a role for both mitotic stalling and increased nuclear incorporation of oxidized nucleotides in karonudib efficacy. In three orthotopic OC patient-derived xenograft models, karonudib monotherapy induced growth delay in vivo. Moreover, addition of karonudib to carboplatin doubled median overall survival in two models and prolonged survival for the duration of the study (110 days) in the third. These results demonstrate activity of mMTH1is as monotherapy and in combination with carboplatin in OC that warrants further investigation.