Abstract Background and objectives: Colorectal cancer (CRC) initiation and progression are governed by complex molecular networks that regulate cell survival and the epithelial-to-mesenchymal transition (EMT). This malignancy remains one of the leading causes of cancer-related mortality worldwide, underscoring the need for novel therapeutic strategies. One promising approach involves the investigation of new molecular entities with enhanced anticancer properties. In this study, we investigated the mechanism of action of a novel hybrid therapeutic candidate, GEM144, which integrates a DNA polymerase-α (POLA1) inhibitor and a histone deacetylase 11 (HDAC11) inhibitor moieties, both reported to play crucial roles in CRC. Methods: Using human CRC cell lines HCT116 and HT29, and “normal-like” human colon cells CCD-841-CoN, proliferation assays were performed to analyze the effect of GEM144 on cell survival in vitro. In addition, CRC xenograft mouse models were used to demonstrate the effect of GEM144 on tumor growth in vivo. Finally, SDS-polyacrylamide gel electrophoresis allowed the identification of molecular pathways that are targeted by GEM144. Results: Our results revealed that GEM144 decreased CRC cell viability in vitro, sparing “normal-like” colon cells. This growth inhibition seemed to be partly relying on apoptosis induction, detected by an increase in the expression of the pro-apoptotic protein Bax when cells were treated with GEM144, at concentrations as low as 1 μM starting 24 hours post-treatment. In addition, GEM144 suppressed the EMT, as evidenced by the upregulation of E-cadherin expression, a key epithelial marker that maintains cell-cell adhesion and epithelial integrity. This was accompanied by a tumor burden reduction in HCT116 xenograft mouse models treated with GEM144. Conclusion: Collectively, these findings provide new insights into the molecular mechanisms underlying the anticancer activity of GEM144 and support its potential as a promising therapeutic candidate for CRC treatment. Citation Format: Rana Abdel-Samad, Avery Lazaro, Maura Mack, Berthe Hayar, Claudio Pisano, Nadine Darwiche. Mechanism of action of GEM144, a POLA1-HDAC11 dual inhibitor, in colorectal cancer models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5707.
Abdel-Samad et al. (Fri,) studied this question.