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

Autor:	Alvarez-Trotta A; Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL, USA.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA., Wang Z; Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL, USA.; Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA., Shersher E; Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL, USA.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA., Li B; Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL, USA.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA., Long J; Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL, USA.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA., Lohse I; Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL, USA.; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA.; Molecular Therapeutics Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA., Wahlestedt C; Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL, USA.; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA., El-Rifai W; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.; Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA., Robbins DJ; Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL, USA.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.; Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.; Co-senior authors., Capobianco AJ; Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL, USA.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.; Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.; Co-senior authors.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2020 Aug 18; Vol. 11 (33), pp. 3174-3187. Date of Electronic Publication: 2020 Aug 18 (Print Publication: 2020).
DOI:	10.18632/oncotarget.27699
Abstrakt:	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. Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare.
Databáze:	MEDLINE
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