Targeting FGFR4 Abrogates HNF1A-driven Metastasis in Pancreatic Ductal Adenocarcinoma.

Purpose: We previously identified an oncogenic role for the transcription factor HNF1A in pancreatic ductal adenocarcinoma (PDAC). However, the role of HNF1A in the metastatic progression of PDAC remains unknown and targeting modalities for HNF1A -dependent phenotypes have yet to be identified. Experimental Design: Transwell chambers were used to assess the effects of HNF1A and FGFR4 modulation on the migration and invasion of ATCC and patient-derived PDAC cells Results: Knockdown of HNF1A significantly decreases and HNF1A overexpression significantly increases PDAC cell migration and invasion. Conclusions: These findings demonstrate that HNF1A drives PDAC metastasis via upregulation of FGFR4, and FGFR4 inhibition is a potential mechanism to target metastasis in PDAC patients. Translational Relevance: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, made even more devastating when metastases overwhelm major organs. The vast majority of PDAC patients either present with metastases or will relapse with recurrent metastatic PDAC after primary tumor resection. Unfortunately, toxic and largely ineffective chemotherapies are currently the only approved treatment options for these patients and therefore there exists a critical and unmet clinical need for targeted therapies against pro-metastatic pathways in PDAC. In the current study, we identify HNF1A as an oncogenic transcription factor that drives metastasis in PDAC, and it does so through upregulation of the receptor tyrosine kinase FGFR4. Importantly, FGFR4 is a targetable vulnerability and treatment with an FGFR4 blocking antibody reduces HNF1A-driven metastasis. These findings suggest that FGFR4 inhibitors could be an efficacious treatment for PDAC patients for the prevention or delay of metastatic tumor development.