Abstract 3304: <i>β</i> , <i>β</i> -dimethylacrylalkannin inhibits colorectal cancer growth <i>in vitro</i> and <i>in vivo</i> by targeted FGFR1

Abstract Background: Colorectal cancer (CRC) continues to be a major global heaith challenge, ranking as a top cause of cancer-related death fatalities. Alarmingly, the five-year survival rate for CRC patients hovers around a mere 10-30%. The disruption of fibroblast growth factor receptor (FGFRs) signaling pathways is significantly implicated in the onset and advancement of colorectal cancer (CRC), presenting a promising target for therapeutic intervention in CRC management. Further investigation is essential to comprehensively elucidate the role of FGFR1 in CRC and to develop effective FGFR1-targeted therapies. Purpose: This study aims to demonstrate the oncogenic role of FGFR1 in colorectal cancer and investigate the potential therapeutic benefits of inhibiting FGFR1 activity using β, β-dimethylacrylalkannin (β,β-DMAA) as an FGFR1 inhibitor. Methods: In the present study, we performed tissue array, kinase profiling analysis assay, computational docking model, knockdown assay to predict and explore the inhibitor of FGFR1. Furthermore, we utilized kinase assay, pull-down, cell proliferation and Patient derived xenograft (PDX) mouse model assays to discover an FGFR1 inhibitor and assess its effects on colorectal cancer growth. Results: In this study, we found that FGFR1 protein is significantly overexpressed in colorectal cancer and plays a pivotal role in regulated cell growth, particularly in colorectal cancer patients. Furthermore, we conducted a computational docking, kinase profiling analysis, simulation and identified that β,β-DMAA could directly bind with FGFR1 within ATP binding pocket domain. Cell-based assays confirmed that β,β-DMAA not only inhibited the growth of colon cancer cells but also induced cell cycle arrest, apoptosis, and the modulation of FGFR1-mediated signaling pathways. Moreover, β,β-DMAA effectively attenuated the growth of PDX tumors in mice that were FGFR1-positive, all without causing significant toxicity. In summary, our study highlights the pivotal role of FGFR1 in colorectal cancer, suggesting that inhibiting FGFR1 activity could be a promising strategy for therapeutic intervention. We present strong evidence that targeting FGFR1 with β,β-DMAA is a viable approach for the management of colorectal cancer. Given its low toxicity and high efficacy, β,β-DMAA, as an FGFR1 inhibitor, warrants further investigation in clinical settings for the treatment of FGFR1-positive tumors. Citation Format: Ran Zhao, Fanxiang Yin, Kangdong Liu, MeeHyun Lee, Zigang Dong. β, β-dimethylacrylalkannin inhibits colorectal cancer growth in vitro and in vivo by targeted FGFR1 [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 3304.