Abstract 6376: Identification and characterization of tumor types that are driven into apoptosis/regression upon treatment with p300/CBP interactome modulator INTH-454

Abstract

Abstract Background: Blockage of the CH1/TAZ1 domain of p300/CBP has a profound effect on cell cycle regulation in cancer cells. A small molecule modulator of CH1/TAZ1, INTH-454, has been shown to trigger cell cycle arrest followed by either cell death or senescence causing sustained anti-tumoral effects in xenograft models of several hard-to-treat tumor types like castration-resistant prostate and gastric cancer. Methods: The anti-proliferative effects of INTH-454 were assessed in a panel of five hundred cancer cell lines. A comprehensive analysis of gene expression and mutational data led to the selection of representative cell lines for subsequent in-depth studies of the corresponding molecular events by cell cycle analysis. INTH-454's impact on genes and proteins involved in cell cycle progression and apoptosis e.g. cyclins and caspases were investigated by qPCR, western blotting and reporter assays. The in vitro results were confirmed in cell line and patient derived xenografts models of gastric and prostate cancer. Results: INTH-454 inhibited cell growth at low nanomolar concentrations in one third of the five hundred cell lines tested. In most of these cell lines, the compound caused cytotoxic effects with >90% inhibition of proliferation at submicromolar concentrations. We used information on tissue origin, gene expression and mutations of the panel to select several cell lines for further characterization. Longitudinal analysis of very sensitive prostate, breast, lung and gastric cancer cell lines showed that the cell cycle was heavily dysregulated. INTH-454 induced cell cycle arrest, generated either strong apoptotic responses or senescence, and caused reduction of protein levels of important cellular factors e.g. c-Myc. Accordingly, INTH-454 treatment caused profound growth inhibition of the tumors in the respective xenograft models under various dosing regimens. Apoptotic/cytotoxic effects in vitro translated into tumor regression while senescence in vitro correlated with tumor stagnation in vivo. Conclusions: INTH-454 exhibits strong anti-proliferative effects in a very broad panel of cancer cell lines. Thorough analysis of particularly responsive genotypes in vitro led to the identification of predictive biomarkers for selection of cell lines that undergo apoptosis upon treatment. These in vitro findings were successfully translated to in vivo xenograft models and will facilitate the identification of patients/cancers that are most susceptible to treatment with INTH-454. Citation Format: Valentino Cattori, Beatrice Pilger, Ulrich Kessler. Identification and characterization of tumor types that are driven into apoptosis/regression upon treatment with p300/CBP interactome modulator INTH-454 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6376.