Repurposing Ceritinib Induces DNA Damage and Enhances PARP Inhibitor Responses in High-Grade Serous Ovarian Carcinoma

Abstract

PARP inhibitors (PARPi) have activity in homologous recombination (HR) repair-deficient, high-grade serous ovarian cancers (HGSOC). However, even responsive tumors develop PARPi resistance, highlighting the need to delay or prevent the appearance of PARPi resistance. Here, we showed that the ALK kinase inhibitor ceritinib synergizes with PARPis by inhibiting complex I of the mitochondrial electron transport chain, which increases production of reactive oxygen species (ROS) and subsequent induction of oxidative DNA damage that is repaired in a PARP-dependent manner. In addition, combined treatment with ceritinib and PARPi synergized in HGSOC cell lines irrespective of HR status, and a combination of ceritinib with the PARPi olaparib induced tumor regression more effectively than olaparib alone in HGSOC patient-derived xenograft (PDX) models. Notably, the ceritinib and olaparib combination was most effective in PDX models with preexisting PARPi sensitivity and was well tolerated. These findings unveil suppression of mitochondrial respiration, accumulation of ROS, and subsequent induction of DNA damage as novel effects of ceritinib. They also suggest that the ceritinib and PARPi combination warrants further investigation as a means to enhance PARPi activity in HGSOC, particularly in tumors with preexisting HR defects. Significance: The kinase inhibitor ceritinib synergizes with PARPi to induce tumor regression in ovarian cancer models, suggesting that ceritinib combined with PARPi may be an effective strategy for treating ovarian cancer.

PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies

“…These mechanisms suggest that ceritinib combined with PARPis may increase its therapeutic efficacy in cancer. The combination of ceritinib and olaparib showed superior cancer inhibition in OC cell lines, and also in the HGSOC PDX model; the results showed that ceritinib monotherapy had no significant effect, but it could increase the therapeutic effect of olaparib in the PDX model ( Kanakkanthara et al, 2022 ), and this result provides the basis for the clinical study on the combination of these two. There is currently no clinical trial to further explore the effect of the combined use of these two drugs on the clinical benefit of patients, which is also the direction of future research.…”

Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer

“…Thus, novel combination strategies are required to efficiently inhibit the growth and development of platinum-resistant OC cells. Recent studies have also demonstrated that the use of olaparib in combination with other agents exerted complementary mechanisms of cytotoxicity [ 44 – 46 ]. Our previous study highlighted the synergistic effects of PARPi and ATO in HR-proficient OC cells [ 47 ].…”

Effects of cancer-associated point mutations on the structure, function, and stability of isocitrate dehydrogenase 2

“…Loss of NADPH deficiency because of IDH2 mutant activity slows down the conversion of oxidized glutathione (GSSG) to reduced glutathione (GSH), which is a major antioxidant against oxidative stress induced by reactive oxygen species (ROS), and this may lead to ROS accumulation and oxidative DNA damage to promote tumor cell growth 23 , 24 . However, the present data showed that overexpression of IDH2 point mutations, except for R172P, reduced ROS levels in 293T cells under normal conditions (Fig.…”