The bromodomain inhibitor IBET-151 attenuates vismodegib-resistant esophageal adenocarcinoma growth through reduction of GLI signaling.

Annamil Alvarez-Trotta,Anthony J Capobianco,Elena Shersher,Jun Long,David J Robbins,Zhiqiang Wang,Bin Li,Wael El-Rifai,Ines Lohse,Claes Wahlestedt

doi:10.18632/oncotarget.27699

Annamil Alvarez-Trotta, Anthony J Capobianco + Show 8 more

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https://doi.org/10.18632/oncotarget.27699

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Abstract

The Hedgehog/GLI (HH/GLI) signaling pathway plays a critical role in human oncogenesis. Unfortunately, the clinical use of HH inhibitor(s) has been associated with serious adverse effects and mutation-related drug resistance. Since the efficacy of SMO (Smoothened) and GLI inhibitors is limited in clinical trials, there remains a critical need for the HH/GLI pathway inhibitors with different mechanisms of action. Here, we show that esophageal adenocarcinoma (EAC) cell lines are insensitive to vismodegib (SMO inhibitor) but respond to GANT61 (GLI1 inhibitor). Furthermore, we examine the role of GLI1 in tumorigenicity of EAC and how a selective bromodomain inhibitor IBET-151 downregulates transcriptional activity of the GLI1 transcription factor in EAC. Our study demonstrates that GLI1 plays an important role in tumorigenicity of EAC and that elevated GLI1 expression in patients’ ultrasound-assisted endoscopic biopsy may predict the response to neoadjuvant chemotherapy (NAC) FOLFOX. Importantly, IBET-151 abrogates the growth of vismodegib-resistant EAC cells and downregulates HH/GLI by reducing the occupancy of BRD4 at the GLI1 locus. IBET-151 also attenuates tumor growth of EAC-PDXs and does so in an on-target manner as it reduces the expression of GLI1. We identify HH/GLI signaling as a novel druggable pathway in EAC as well as validate an ability of clinically relevant GLI inhibitor to attenuate the viability of vismodegib-resistant EAC cells. Therefore, we propose that selective bromodomain inhibitors, such as IBET-151, could be used as novel therapeutic agents for EAC patients harboring GLI-dependent tumors.

Highlights

Esophageal adenocarcinoma (EAC) is one of the most aggressive cancers in the world that is characterized by a high mortality rate and poor prognosis [1]
Positive levels of GLI1 were observed in 77% (22/28) of poorly-differentiated EAC tumors, whereas mild positive nuclear staining for GLI1 was observed in 46% (15/32) of the well and moderately differentiated EAC cases (Figure 2B) We determined that GLI1 levels vary depending on the clinical stage (Figure 2C) and lymph node metastasis of EAC tumors (Figure 2D), increasing with the stage of the disease
In order to determine whether GLI1 played a role in the response to neoadjuvant chemotherapy (NAC) FOLFOX, we analyzed the expression of GLI1 in a set of chemo-naive EAC samples derived from ultrasound-assisted endoscopic biopsies and determined its correlation to the pathological response to NAC

Summary

Introduction

Esophageal adenocarcinoma (EAC) is one of the most aggressive cancers in the world that is characterized by a high mortality rate and poor prognosis [1]. The incidence of EAC has been on the rise in the United States and other western countries over the past 30 years [2]. EAC remains a virulent disease with an overall 5-year survival rate < 20% [1, 2]. The relationship between HH signaling and therapeutic response is unknown. The HH pathway and associated overexpression of GLI1 have been reported as oncogenic [4] while the nuclear expression of GLI1 is considered predictive of a pathologic complete response to chemoradiation in esophageal cancer (EC) [5]. There have been some advances in the discovery of molecular drivers of EC, a detailed understanding of the molecular mechanisms that promote EAC progression is still limited

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