Abstract 4752: HMGA1: An epigenetic driver of colon carcinogenesis by inducing FGF19 signals which can be targeted with FGFR4 receptor blockade

Abstract Advanced colorectal cancer (CRC) continues to be a significant healthcare burden with increasing incidence in younger patients, necessitating the development of novel targeted therapies. The gene encoding the High Mobility Group A1 (HMGA1) chromatin regulator is enriched in adult stem cells, including colon stem cells, and diverse tumors where high levels portend adverse clinical outcomes. Indeed, HMGA1 is among the genes most highly overexpressed in CRC compared to nonmalignant colon epithelium. To define targetable mechanisms underlying HMGA1 in colon carcinogenesis, we performed gene expression studies (bulk, single cell RNA sequencing) and chromatin accessibility assays (ATACseq) in preclinical models and human tumors which unveiled the FGF19 growth factor as a downstream effector of HMGA1 in CRC. We had previously discovered that disrupting FGF19 signaling with the clinical inhibitor to the FGFR4 receptor (BLU9931) in KPC mouse models of pancreatic cancer and human orthotopic xenografts decreases pancreatic tumor and stroma formation while prolonging survival. In mice with intestinal epithelial cells harboring Adenomatous polyposis coli (ApcMin) inactivation, we found that Hmga1 is induced following inoculation with enterotoxigenic Bacteroides fragilis (ETBF), a common oncogenic bacterium in humans with CRC. In this model, ETBF inoculation results in robust distal colon tumorigenesis and HMGA1-dependent amplification of Wnt signaling. HMGA1 also activates murine FGF19 (Fgf15) expression. Strikingly, in human CRC tumors, HMGA1 and FGF19 are also up-regulated and positively correlated (r=0.71, P0.00001; TCGA). Further, silencing HMGA1 in human CRC cell lines (SW620) represses FGF19 expression. By ATACseq in mouse colon crypt cells with Apc inactivation, HMGA1 enhances chromatin accessibility at the murine Fgf15 locus (P0.001), suggesting that HMGA1 opens chromatin to activate Fgf15 expression. We therefore tested whether FGFR4 inhibition has anti-tumor efficacy in CRC by treating human CRC cells (SW620) with BLU9931. FGFR4 blockade disrupts clonogenicity in a dose-dependent fashion, recapitulating effects of HMGA1 silencing. Together, these data illuminate the HMGA1-FGF19 axis as a novel epigenetic pathway driving colon carcinogenesis and a promising therapeutic target. Citation Format: Yuze Du, Li Luo, Jung-Hyun Kim, Bailey West, Tatianna Larman, Leslie Cope, Eric R. Fearon, Cynthia Sears, Linda Resar. HMGA1: An epigenetic driver of colon carcinogenesis by inducing FGF19 signals which can be targeted with FGFR4 receptor blockade 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 4752.