Abstract 390: Prostate cancer progression depends on the activity of the mitotic kinase citron kinase

Abstract

Abstract Androgen receptor (AR) is the major driver of prostate cancer (CaP) progression. Despite initially inducing remissions, androgen deprivation therapy (ADT) does not cure CaP and the majority of CaP that recurs under ADT continues to rely on AR. In a subset of patients, administration of novel, more potent ADT drugs leads to emergence of a neuroendocrine (NE) CaP phenotype that is AR-indifferent and even harder to treat. The molecular mechanisms by which AR regulates cell cycle progression and that can be developed into alternative targets to inhibit CaP growth, overcome acquired resistance to ADT, or prevent NE progression, however, remain largely unknown. Here, we identify citron kinase (CIT), which controls cell division, as a novel drugabble target that acts downstream of AR. In multiple CaP models, CIT protein expression was stimulated selectively by low doses of androgens that promote CaP cell proliferation and decreased by AR silencing or short-term administration of AR-antagonist enzalutamide, confirming its AR dependence. Silencing of CIT significantly reduced CaP cell viability and cell proliferation, delayed cell progression, increased the number of multinucleated cells in ADT-naïve and -recurrent CaP cells, and attenuated CaP growth in xenograft models. Overexpression of CIT, transiently or stably, stimulated CaP cell proliferation in androgen-supplemented conditions and under ADT, and this depended entirely on an intact CIT kinase domain. In 2 independent clinical CaP datasets, CIT mRNA levels increased during CaP progression and higher CIT expression correlated with shorter disease-free and overall survival. Using CaP tissue microarrays that contain more than 200 patient specimens, CIT protein expression was significantly higher in primary CaP when compared to adjacent non-neoplastic prostate tissues and correlated with increasing Gleason scores, validating the relevance of CIT overexpression to CaP aggressiveness. Integrated RNA-Seq, MSigDB and GSEA analyses confirmed that the AR- and CIT-dependent transcriptome preferentially controlled CaP cell cycle progression and proliferation. Mechanistically, the use of inhibitors of gene transcription, mRNA translation and proteasome indicated that the androgen-dependence of CIT expression is regulated at the post-transcriptional level. Specifically, CIT protein expression was controlled by the E2F family of cell cycle regulators, with androgen-responsive E2F2 as the major determinant of CaP CIT expression. Our work, thus, isolated a novel role for the mitotic kinase CIT in AR-dependent CaP cell proliferation and clinical progression and identified CIT’s kinase moiety as a novel target for CaP therapy. Funding: NIH/NCI, Case Comprehensive Cancer Center Pilot Research Award Citation Format: Salma Ben-Salem, Salam Bachour, Varadha Balaji Venkadakrishnan, Yixue Su, Eduardo Cortes Gomez, Qiang Hu, Eric Klein, Nicolas Marlo, Cristina Magi-Galluzzi, Liu Song, Hannelore V. Heemers. Prostate cancer progression depends on the activity of the mitotic kinase citron kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 390.