Abstract 1158: The HDAC inhibitor domatinostat (4SC-202) sensitizes pancreatic cancer to chemotherapy by targeting cancer stem cell compartment via FOXM1 modulation
Authors: Roca Maria S. , Moccia Tania , Testa Cristina , Iannelli Federica , Vitagliano Carlo , Di Gennaro Elena , Bruzzese Francesca , Leone Alessandra , Budillon Alfredo 
Published: July 2021

Abstract
Pancreatic cancer (PCa) is the fourth leading cause of cancer-related death in developed countries, and, although chemotherapeutic regimens, such as FOLFIRINOX or gemcitabine combined with nab-paclitaxel (GP), improved overall survival in metastatic setting, the prognosis remains very poor with 5-year survival rate of 8%. Here, we investigated the potential of domatinostat (4SC-202), a new class I histone deacetylase (HDAC) inhibitor, currently in clinical development, to sensitize pancreatic cancer cells to chemotherapy. We first demonstrated the synergistic/additive anti-tumor effects induced by domatinostat plus commonly used chemotherapeutics in PCa (i.e. gemcitabine, paclitaxel, irinotecan, oxaliplatin, fluoropyrimidines) or their combinations, in three PCa models (PANC1, PANC28 and ASPC1) by evaluating combination indexes (Chou and Talalay). Then, we explored in details the combination of domatinostat plus GP regimen, confirming the strong synergistic anti-tumor interaction by evaluating apoptosis, clonogenic capability as well as PANC1 and PANC28 in vivo xenograft tumor growth. We hypothesize that domatinostat could potentiate GP by targeting cancer stem cell (CSC) compartment. Indeed, domatinostat inhibited pancreatic cancer sphere formation and down-regulated stem cell markers, such as Oct-4 and CD133, both in vitro and in vivo. Moreover, domatinostat induced mitochondrial and cellular oxidative stress in CSC sub-population by increasing reactive oxygen species levels. Mechanistically, we speculate that domatinostat modulates the expression and function of forkhead box M1 (FOXM1), a transcriptional factor playing a crucial role in stemness and oxidative stress modulation. Notably, domatinostat downregulated FOXM1 at mRNA and protein level as well as increased FOXM1-acetylation, thus preventing nuclear translocation and inducing proteasome-mediated protein degradation. FOXM1 down-regulation correlated with a reduction of anti-oxidative FOXM1-regulating genes such as Sod2, Catalase and Gpx2. Furthermore, by overexpressing FOXM1 in PCa cells we reduced domatinostat-inducing oxidative mitochondrial and cellular stress as well as GP sensitization, both in adherent and spheroid cell growth conditions. Finally, we found a correlation of FOXM1 expression with poor progression free survival in PCa chemotherapy-treated patients by analyzing TCGA PAAD data. Overall, we suggest a novel therapeutic strategy based on domatinostat to improve efficacy and to overcome resistance of commonly used chemotherapeutics in pancreatic cancer that warrant further clinical evaluation.
Citation Format: Maria S. Roca, Tania Moccia, Cristina Testa, Federica Iannelli, Carlo Vitagliano, Elena Di Gennaro, Francesca Bruzzese, Alessandra Leone, Alfredo Budillon. The HDAC inhibitor domatinostat (4SC-202) sensitizes pancreatic cancer to chemotherapy by targeting cancer stem cell compartment via FOXM1 modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1158.