Abstract 1020: p300 and CBP targeting in castration therapy resistant prostate cancer

Abstract

Abstract p300 and CBP interact with transcription factors and other proteins via their histone acetyltransferase domain (HAT) and a bromodomain (Bd). In prostate cancer, p300 and CBP act as oncogenes and are commonly upregulated. p300 and CBP are valid targets for therapy due to their function as androgen receptor (AR) coactivators and involvement in castration resistance. Revealing downstream pathways and their function in cancer cell proliferation and resistance should further identify potential novel therapeutic targets. The effect of the p300/CBP HAT inhibitor C646 and the Bd inhibitor ICBP-112 on viability was tested. To this end several human PCa cell lines with different AR expression levels and resistance status were used. The resistant cells were derived from DUCaP, LAPC4 and LNCaP cells chronically treated with Enzalutamide (DUCaP ENZA, LAPC4 ENZA and LNCaP ABL ENZA). Resistance was verified by viability assay. Regulation of AR downstream targets was studied by qRT-PCR and Western blot. Gene expression in the different DUCaP and LNCaP sublines after inhibitor treatment was analyzed with RNAseq. Both inhibitors exhibited IC50 values on viability at micromolar concentrations with a significantly lesser effect on androgen-insensitive PC3 cells compared to AR sensitive cells. Significantly increased sensitivity to inhibitors was observed in enzalutamide-resistant DUCaP ENZA, LAPC4 ENZA and LNCaP ABL ENZA cell lines relative to parental cells: respectively 1.83- (*), 2- (*) and 2.7-fold (*) for C646 and not significant, 1.8- (p<0.1) and 1.56-fold (*) for ICBP-112. Moreover, ICBP-112 treatment of DUCaP cells significantly reduced expression of the AR target genes FKBP5, PSA and TMPRSS2 0.6- (**), 0.57- (**) and 0.37-fold (***) respectively. Similar results were obtained with DUCaP ENZA cells 0.46- (*), 0.45- (*) and 0.57-fold (ns) for FKBP5, PSA and TMPRSS2, respectively. Whilst less pronounced, this regulation was also observed at the protein level. Similar results were obtained with C646. RNAseq results suggest multiple changes in sublines after chronic enzalutamide treatment in DUCaP and LNCaP cells. Inhibition of p300 and CBP reduced androgen-, myc- and parts of an EMT-signature, which are likely involved in the development of enzalutamide resistance. Taken together, C646 and ICBP-112 are effective inhibitors of AR dependent PCa. Furthermore, differences between cell lines suggest that the AR background and other factors influence the inhibitor effectivity. A significantly increased effect of the HAT and Bd inhibitors in CRPC suggests an important role for p300/CBP in CRPC. Citation Format: Tobias Furlan, Natalie Sampson, Frédéric R. Santer, Zoran Culig. p300 and CBP targeting in castration therapy resistant prostate cancer [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 1020.