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

Autor:	Kanakkanthara A; Department of Oncology, Mayo Clinic, Rochester, Minnesota. karnitz.larry@mayo.edu Weroha.Saravut@mayo.edu Kanakkanthara.Arun@mayo.edu.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota., Hou X; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Ekstrom TL; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Zanfagnin V; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Huehls AM; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Kelly RL; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota., Ding H; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Larson MC; Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota., Vasmatzis G; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota., Oberg AL; Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, Minnesota., Kaufmann SH; Department of Oncology, Mayo Clinic, Rochester, Minnesota.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota., Mansfield AS; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Weroha SJ; Department of Oncology, Mayo Clinic, Rochester, Minnesota. karnitz.larry@mayo.edu Weroha.Saravut@mayo.edu Kanakkanthara.Arun@mayo.edu., Karnitz LM; Department of Oncology, Mayo Clinic, Rochester, Minnesota. karnitz.larry@mayo.edu Weroha.Saravut@mayo.edu Kanakkanthara.Arun@mayo.edu.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2022 Jan 15; Vol. 82 (2), pp. 307-319. Date of Electronic Publication: 2021 Nov 22.
DOI:	10.1158/0008-5472.CAN-21-0732
Abstrakt:	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. (©2021 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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