Abstract 445: Determining the molecular and biologic effects of HER3 and IDH1 antagonism on liver endothelium-PDAC crosstalk
Authors: Boutros Christina S. , Loftus Alexander W. , Rathore Moeez , Zarei Mehrdad , Curry Kimberly , Winter Jordan M. , Wang Rui 
Published: March 2024

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy due to the lack of early diagnosis and limited response to treatments. Austere and nutrient-deprived conditions typically present in the PDAC tumor microenvironment (TME) induce chemotherapy resistance. Therefore, novel therapeutic strategies are needed. We have previously demonstrated the primary tumor expresses IDH1 which supports the pro-survival oxidative phosphorylation (OXPHOS) metabolism, and has been successfully targeted by ivosidenib, an IDH1 inhibitor, in preclinical studies. Meanwhile, endothelial cells (ECs) from the liver, the most common site of PDAC metastases, secrete soluble factors in the conditioned medium (CM) that activate HER3, a receptor tyrosine kinase, involved in cell proliferation and metabolism.

OBJECTIVES: We sought to (1) uncover the mechanisms involved in driving the metabolic differences between primary and metastatic tumors through the utilization of ECs from the liver (2) conduct metabolic analyses to determine metabolic effects of HER3 activation, and (3) examine potential synergism of combination therapy against HER3 and IDH1 in primary and metastatic niches. METHODS: The effect of CM on PDAC cell growth was determined by PICO Green Assay. The effects of ECs HER3/IDH1 inhibitions on cellular metabolism were measured by multiple metabolic assays including Seahorse, CellTiter-Glo, lactate ELISA, and TMRE assays. HER3-specific antibody Seribantumab, HER3 inhibitor Sapitanib, and IDH1 inhibitor ivosidenib were used to block HER3 and/or IDH1. Moreover. A cell viability-based synergy study was performed to assess the effects of HER3-IDH1 combination. Effects of HER3 and IDH1 inhibitions on PDAC tumor growth and mouse survival in vivo were determined in syngeneic, orthotopic models with PDAC primary tumors and liver metastases.

RESULTS: CM from liver ECs significantly increased cell growth in PDAC cells in vitro and increased glycolytic tropism in multiple HER3 positive PDAC cell lines measured by metabolic assays mentioned above. HER3 antibody and HER3 inhibitor both increased oxidative consumption rate (OCR), an indirect measure of OXPHOS, and decreased extracellular acidification rate (ECAR), a measure of glycolysis measured by Seahorse. Combination therapy utilizing HER3 and IDH1 inhibitors revealed synergy. In our in vivo tumor model, mice treated with combination therapy had significantly longer overall survival than those given either monotherapy or no treatment.

CONCLUSIONS: Our results demonstrated a paracrine role of liver ECs in promoting cell growth via activating HER3 in PDAC cells as well as reprograming cellular metabolism from OXPHOS towards glycolysis. Identification of the metabolic shift that takes place in metastatic PDAC to the liver due to HER3 activation gives way for the development of a potentially lethal drug combination.

Citation Format: Christina S. Boutros, Alexander W. Loftus, Moeez Rathore, Mehrdad Zarei, Kimberly Curry, Jordan M. Winter, Rui Wang. Determining the molecular and biologic effects of HER3 and IDH1 antagonism on liver endothelium-PDAC crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 445.