1. Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype
- Author
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Anna Cvrljevic, Heini Lassus, Teemu D. Laajala, Tove J. Grönroos, Denise C. Connolly, Umar Butt, Kaisa Huhtinen, Katja Kaipio, T. Arsiola, Ari Ristimäki, Olli Carpén, Jeroen Pouwels, Jukka Westermarck, Camilla Böckelman, Research Program in Systems Oncology, University of Helsinki, Research Programs Unit, Department of Surgery, HUS Abdominal Center, Clinicum, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, HUSLAB, Department of Pathology, ATG - Applied Tumor Genomics, HUS Diagnostic Center, II kirurgian klinikka, CAN-PRO - Translational Cancer Medicine Program, Olli Mikael Carpen / Principal Investigator, and Precision Cancer Pathology
- Subjects
Quinuclidines ,Cancer Research ,endocrine system diseases ,Combination therapy ,medicine.medical_treatment ,3122 Cancers ,Carcinoma, Ovarian Epithelial ,Autoantigens ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Animals ,Humans ,Medicine ,030304 developmental biology ,Ovarian Neoplasms ,chemistry.chemical_classification ,0303 health sciences ,Chemotherapy ,Reactive oxygen species ,business.industry ,NF-kappa B ,medicine.disease ,Phenotype ,female genital diseases and pregnancy complications ,In vitro ,3. Good health ,Oncology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Female ,3111 Biomedicine ,business ,Ovarian cancer - Abstract
Identification of ovarian cancer (OvCa) patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high grade OvCa tumors at diagnosis express CIP2A oncoprotein at low levels. CIP2Alow OvCa tumors have significantly lower likelihood of disease relapse after standard chemotherapy, but yet a portion of relapsed tumors retain their CIP2Alow phenotype. We further discover that reactive oxygen species (ROS) inducing compound APR-246 (PRIMA-1Met/Eprenetapopt), currently in clinical development, preferentially kill CIP2Alow OvCa cells across multiple chemotherapy resistant cell lines. Consistent with CIP2Alow OvCa subtype in humans, CIP2A is dispensable for development of MISIIR-TAg-driven mouse OvCa tumors. Nevertheless, CIP2A deficient OvCa tumor cells from MISIIR-TAg mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the OvCa cells to APR-246 by inhibition of NF-kB activity. Accordingly, combination of APR-246 and Nf-kB inhibitor compounds strongly synergized in killing of CIP2A positive OvCa cells. Collectively, we discover low CIP2A expression as a vulnerability for APR-246 in OvCa. The results warrant consideration of clinical testing of APR-246 for CIP2Alow OvCa tumor subtype patients, and reveal CIP2A as a candidate APR-246 combination therapy target.
- Published
- 2021
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