Clinical candidate and genistein analogue AXP107-11 has chemoenhancing functions in pancreatic adenocarcinoma through G protein-coupled estrogen receptor signaling.

Fahmi Mesmar,Chin‐Yo Lin,Bingbing Dai,Michael Kim,Mohammed Hakim Jafferali,Anders Berkenstam,Yang Zhao,Jing Wang,Jithesh Jose Augustine,Jason Fleming,Linnea Hases,Cecilia Williams,Ya'An Kang,Sebastian Dilorenzo,Ahmed Ibrahim

doi:10.1002/cam4.2581

Abstract

Despite advances in cancer therapeutics, pancreatic cancer remains difficult to treat and often develops resistance to chemotherapies. We have evaluated a bioavailable genistein analogue, AXP107‐11 which has completed phase Ib clinical trial, as an approach to sensitize tumor cells to chemotherapy. Using organotypic cultures of 14 patient‐derived xenografts (PDX) of pancreatic ductal adenocarcinoma, we found that addition of AXP107‐11 indeed sensitized 57% of cases to gemcitabine treatment. Results were validated using PDX models in vivo. Further, RNA‐Seq from responsive and unresponsive tumors proposed a 41‐gene treatment‐predictive signature. Functional and molecular assays were performed in cell lines and demonstrated that the effect was synergistic. Transcriptome analysis indicated activation of G‐protein‐coupled estrogen receptor (GPER1) as the main underlying mechanism of action, which was corroborated using GPER1‐selective agonists and antagonists. GPER1 expression in pancreatic tumors was indicative of survival, and our study proposes that activation of GPER1 may constitute a new avenue for pancreatic cancer therapeutics.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the third‐most common cause of cancer‐related mortality in the United States
We suggest that the chemoenhancing mechanism of action include activation of GPER1, that mediates a synergistic effect when combined with gemcitabine
Preclinical studies have indicated that genistein have chemoenhancing effects but its efficacy has essentially been unexplored and its precise mechanism of action in PDAC is not known.[13]

Summary

| INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) is the third‐most common cause of cancer‐related mortality in the United States. In order to provide a comprehensive understanding of the molecular mechanism of action of genistein and AXP107‐11 in PDAC, we performed gene expression profiling using RNA sequencing (RNA‐Seq) and functional and mechanistic experiments in cell lines. Based on this data, we suggest that the chemoenhancing mechanism of action include activation of GPER1, that mediates a synergistic effect when combined with gemcitabine

| MATERIALS AND METHODS

| RESULTS

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Findings

| DISCUSSION