beta , beta -dimethylacrylalkannin inhibits colorectal cancer growth in vitro and in vivo by targeted FGFR1

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 beta , beta -dimethylacrylalkannin ( beta , beta -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 beta , beta -DMAA could directly bind with FGFR1 within ATP binding pocket domain. Cell-based assays confirmed that beta , beta -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, beta , beta -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 beta , beta -DMAA is a viable approach for the management of colorectal cancer. Given its low toxicity and high efficacy, beta , beta -DMAA, as an FGFR1 inhibitor, warrants further investigation in clinical settings for the treatment of FGFR1-positive tumors.