Abstract C076: New insights into the role of FOXA1- HNF4 axis in pancreatic cancer

Abstract

Abstract Despite recent advances in the treatment of pancreatic adenocarcinoma (PDAC), the median survival remains <12 months. Patients typically present with late-stage disease and have limited treatment options. Therefore, there is an immediate need for the generation of new and innovative therapeutic targets. Little is known about the role of pioneer factors such as FOXA1 and their interaction partners in a PDAC context. Inspired by literature reports implicating FOXA1 and GATA5/GATA6 in regulating pancreatic cancer resistance and metastasis, our study hypothesised the possibility of an undiscovered nuclear receptor that works with FOXA1 (similar to Estrogen receptor in breast cancer). Using innovative ‘omic’ based approaches (RIME) developed in our laboratory 1 we discovered a nuclear receptor (NR) complex involving HNF4A and HNF4G in the classical sub-type of pancreatic cancer. Subsequently the interaction was independently validated in Whipple surgical biopsies from PDAC patients using ChIP-sequencing studies. Across multiple patient tumors (n=7) a binding overlap specifically between FOXA1 and HNF4G (3461 sites) was established. To investigate the therapeutic potential of HNF4G in the classical subtype of PDAC, we generated CRISPR deletions (KO) of HNF4G in the HPAF-II cells. HNF4G-KO cells were orthotopically implanted into the pancreas of NSG mice. A significant survival advantage of 12 days (<0.001) and reduced growth (<0.02) was observed in these mice compared to the controls. To better understand the impact of HNF4G-KO on gene expression, the orthotopic tumors were subjected to RNA-seq analyses. Gene set enrichment and pathway analysis revealed significantly down-regulated pathways to include EMT transition. TCGA data highlighted HNF4G amplification in 9% of PDAC patients with concomitant decreased progression free survival. These data point towards HNF4G being a therapeutically viable target for further exploration. Protein Arginine Methyl Transferase 1 (PRMT1) is a common interactor of both FOXA1 and HNF4G. Our study reveals a unique dependency of PRMT1 on the HNF4G-FOXA1 complex in PDAC biopsies. HNF4G-KO drastically reduces the chromatin binding of PRMT1, implicating them as functionally dependent. Treatment of HNF4G-KO cells with GSK3368715 (PRMT1 inhibitor) further sensitizes these cells and results in a significant survival advantage (10 days <0.02). We propose a model of HNF4G inhibition in combination with PRMT1 as a novel therapeutic opportunity to treat the classical sub-type of PDAC. Further, our study reveals a unique reliance of primary classical tumors on HNF4G. Although HNF4G appears to dominate FOXA1 functionality in the primary disease, FOXA1 remains instrumental in priming metastasis and enhancer reprograming. 1. Papachristou EK, Kishore K, Holding AN, Harvey K, Roumeliotis TI, Chilamakuri CSR, et al. A quantitative mass spectrometry-based approach to monitor the dynamics of endogenous chromatin-associated protein complexes. Nature Communications. 2018;9(1):2311. Citation Format: Shalini V. Rao, Lisa Young, Danya Cheeseman, Stephanie Mack, Jill Temple, Chandra Shekar Reddy Chilamakuri, Evangelia Papachristou, Catherina Pelicano, Amy Smith, Dominique-Laurent Couturier, Michael Gill, Duncan Jodrell Jodrell, Alasdair Russell, Igor Chernukhin, Jason Carroll. New insights into the role of FOXA1- HNF4 axis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C076.