Language

English

Publication Date

8-4-2026

Journal

Molecular Cancer Therapeutics

DOI

10.1158/1535-7163.MCT-25-0798

PMID

41670299

PMCID

PMC13036806

PubMedCentral® Posted Date

4-1-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Ewing sarcoma is a rare and aggressive pediatric malignancy with limited therapeutic options, particularly for relapsed or refractory cases, highlighting the urgent need for innovative treatment strategies. In this study, we identify endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) as critical therapeutic vulnerabilities in Ewing sarcoma and introduce 4-(heptyloxy)phenol (AC-45594) as a novel small-molecule agent that exploits these stress pathways. AC-45594 selectively inhibited the growth of Ewing sarcoma cells among 13 cancer and 6 noncancerous cell lines, demonstrating marked tumor specificity. Structure-activity relationship studies revealed that both the phenolic hydroxyl group and an optimal alkoxy chain length (7-9 carbon atoms) are essential for its activity. Mechanistically, AC-45594 induces ERS, activates UPR, and drives a shift from adaptive to terminal stress signaling, culminating in apoptosis of Ewing sarcoma cells. Proteomic and gene expression analyses further supported the selective activation of proapoptotic UPR signaling. These findings establish ERS and UPR as actionable targets in Ewing sarcoma and position AC-45594 as a first-in-class compound capable of selectively inducing stress-driven cell death. This work lays the foundation for a new class of therapeutics targeting maladaptive stress responses in pediatric sarcomas and potentially other hard-to-treat cancers.

Keywords

Humans, Unfolded Protein Response, Sarcoma, Ewing, Apoptosis, Cell Line, Tumor, Phenols, Signal Transduction, Endoplasmic Reticulum Stress, Antineoplastic Agents, Cell Proliferation, 4-(heptyloxy)phenol, AC-45594, Ewing Sarcoma, Endoplasmic Reticulum (ER) Stress, Unfolded Protein Response (UPR), Apoptosis

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.