@article{67d5a1b41c9d493eac83f97fc9a2ad2d,
title = "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.",
author = "Arun Kanakkanthara and Xiaonan Hou and Ekstrom, {Thomas L.} and Valentina Zanfagnin and Huehls, {Amelia M.} and Kelly, {Rebecca L.} and Husheng Ding and Larson, {Melissa C.} and George Vasmatzis and Oberg, {Ann L.} and Kaufmann, {Scott H.} and Mansfield, {Aaron S.} and Weroha, {S. John} and Karnitz, {Larry M.}",
note = "Funding Information: G. Vasmatzis reports other support from WholeGenome LLC outside the submitted work. A.L. Oberg reports grants from NCI during the conduct of the study. S.H. Kaufmann reports grants from National Cancer Institute during the conduct of the study; as well as reports nonfinancial support from Clovis Oncology outside the submitted work; as well as a patent for mechanisms of resistance to PARP inhibitors issued. A.S. Mansfield reports grants from Novartis during the conduct of the study; Funding Information: and other support from Genentech, Abbvie, BMS, Janssen, and grants from Mark Foundation, NIH, Department of Defense, and other support from Shanghai Roche Pharmaceuticals outside the submitted work; and nonremunerated director of the Mesothelioma Applied Research Foundation. S. Weroha reports personal fees from Kiyatec outside the submitted work. L.M. Karnitz reports grants from NIH during the conduct of the study. No disclosures were reported by the other authors. Funding Information: This work was supported by NIH (R01 CA194498 to L.M. Karnitz), a Mayo Clinic Ovarian Cancer SPORE Developmental Award (P50 CA136393 to L.M. Karnitz and A. Kanakkanthara), a Mayo Clinic Ovarian Cancer SPORE Career Enhancement Award (P50 CA136393 to A. Kanakkanthara), a Foundation for Women{\textquoteright}s Cancer Genentech Ovarian Cancer Young Investigator Career Development Award (to A. Kanakkanthara), and a Wallace and Evelyn Simmers Career Development Award for Ovarian Cancer Research (to A. Kanakkanthara), a Minnesota Ovarian Cancer Alliance grant (to V. Zanfagnin), Ovarian Cancer Research Alliance Liz Tilberis Early Career Award (to S.J. Weroha), and funding from the Novartis Investigator Initiated Studies Program (to A.S. Mansfield and S.J. Weroha). The authors also thank Paul Haluska and Marc A. Becker for providing RNA-seq data. Publisher Copyright: 2021 The Authors; Published by the American Association for Cancer Research",
year = "2022",
month = jan,
day = "15",
doi = "10.1158/0008-5472.CAN-21-0732",
language = "English (US)",
volume = "82",
pages = "307--319",
journal = "Cancer Research",
issn = "0008-5472",
number = "2",
}