Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype

Cvrljevic, A. N.; Butt, U.; Huhtinen, K.; Gronroos, T.; Bockelman, C.; Lassus, H.; Kaipio, K.; Ristimaki, A.; Arsiola, T.; Laajala, T. D.; Connolly, D.; Carpen, O.; Pouwels, J.; Westermarck, J.

doi:10.1101/2021.03.31.437804

bioRxiv · 10.1101/2021.03.31.437804

Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype

Cvrljevic, A. N.·Butt, U.·Huhtinen, K.·Gronroos, T.·Bockelman, C.·Lassus, H.·Kaipio, K.·Ristimaki, A.·Arsiola, T.·Laajala, T. D.·Connolly, D.·Carpen, O.·Pouwels, J.·Westermarck, J.

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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.

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Cvrljevic, A. N., Butt, U., Huhtinen, K., Gronroos, T., Bockelman, C., Lassus, H., Kaipio, K., Ristimaki, A., Arsiola, T., Laajala, T. D., Connolly, D., Carpen, O., Pouwels, J., Westermarck, J.. 2021-03-31. Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype. https://doi.org/10.1101/2021.03.31.437804

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