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. Further, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient OvCa cells, we identified reactive oxygen species inducer APR-246, tested previously in OvCa clinical trials. Consistent with CIP2A-deficient OvCa subtype in humans, CIP2A is dispensable for development of MISIIR-Tag-driven mouse OvCa tumors. Nevertheless, CIP2A null 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, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient OvCa tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.

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