Abstract 4220: Anticancer effects of GEM144, a novel POLA1-HDAC11 dual inhibitor, on colorectal cancer models

Abstract Background and Objectives: Colorectal cancer (CRC) is the third most occurring cancer and the second cause of cancer-related deaths. Despite decades of research fighting the progression of CRC and the development of many therapeutic compounds, the 5-year survival rate remains at around 64%, with worse prognosis at advanced stages of the disease. The search for a fully efficacious treatment for CRC thus endures, in light of these suboptimal prognostic figures. GEM144 is a novel compound that was recently synthesized as a dual inhibitor of the DNA polymerase alpha (POLA1) and the histone deacetylase 11 (HDAC11). Initial investigations showed pronounced anti-proliferative potential of GEM144 when screened on a panel of hematological and solid cancer cells. Our study aims at examining the anticancer properties of GEM144 on CRC models. Methods: We used two human CRC cell lines, HCT116 and HT29, derived from human colorectal carcinoma and adenocarcinoma, respectively, and one colon cell line, CCD-841-CoN, derived from the colon of a healthy subject. MTT assay [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] was used to assess cell growth, and trypan blue dye exclusion assay to evaluate cell viability. A wound healing assay was performed to investigate the effect of GEM144 on cell migration ability. Finally, the in vivo effect of GEM144 on tumor growth inhibition was analyzed in CRC xenograft nude mouse models. Results: GEM144 decreased the growth of HCT116 and HT29 cells at 1 μM and 5 μM, respectively, starting at 24 hours post-treatment. This inhibition was more pronounced after 72 hours of treatment, where growth rate was less than 10% compared to control cells for both cell lines. Trypan blue exclusion assay showed comparable results for both cell lines, suggesting a reduction in cell viability. Interestingly, up to 10 μM of GEM144 had no effect on the growth of the normal-like CCD-841-CoN cells. GEM144 had an inhibitory effect on the migration of the HCT116 cells, evident by the reduction of wound healing in GEM144-treated cells compared to control ones. Finally, GEM144 showed around 20% relative decrease in the tumor volume of HCT116 xenograft mice treated with oral GEM144 compared to mice receiving the vehicle, without affecting body weight. Remarkably, GEM144 sensitized the tumor to cisplatin, a standard drug in the treatment of CRC. In fact, while cisplatin reduced tumor volume by 46%, a combination of cisplatin and GEM144 reduced tumor volume by 58%. Conclusion: Our data show promising effects of GEM144 as an anti-cancer compound in the treatment of CRC cell lines and in mouse models. Our study will now further focus on understanding the mechanisms of action of GEM144 on cell cycle progression and on the expression of major players in colorectal carcinogenesis. Citation Format: Rana Abdel-Samad, Susanna Noonan, Aileen Benitez, Teagan Mattox, Berthe Hayar, Sabrina Dallavalle, Claudio Pisano, Nadine Darwiche. Anticancer effects of GEM144, a novel POLA1-HDAC11 dual inhibitor, on colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4220.