ERX-208 Induces Endoplasmic Reticulum Stress and Suppresses DNA Damage Repair to Enhance Chemotherapy Sensitivity
5 affiliations
- 1Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
- 2Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas.
- 3Mays Cancer Center, San Antonio, Texas.
- 4EtiraRx, Dallas, Texas.
- 5Audie L. Murphy South Texas Veterans Health Care System, San Antonio, Texas.
Abstract
Ovarian cancer remains the most lethal gynecologic malignancy, driven in part by intrinsic and acquired therapeutic resistance to DNA-damaging chemotherapies. We previously demonstrated that ERX-208 targets the protein encoded by lysosomal acid lipase to induce catastrophic endoplasmic reticulum (ER) stress in ovarian cancer models. As ERX-class compounds advance to clinical development, rational combination strategies are needed to maximize therapeutic efficacy. To address this question, we conducted an unbiased in vitro screen of the combination of ERX-208 with 147 FDA-approved agents. We identified that DNA-damaging chemotherapies, including anthracyclines, oxaliplatin, and paclitaxel, were most synergistic in combination with ERX-208. Reanalysis of our transcriptomic data in ovarian cancer cells revealed coordinated suppression of DNA damage repair, DNA replication, and checkpoint pathways following ERX-208 treatment. Together, these data support a narrative that ERX-208 may selectively suppress DNA repair pathways and potentiate cytotoxicity by DNA-damaging agents. To test this hypothesis, we used platinum and paclitaxel, two standard-of-care agents in ovarian cancer. We found that ERX-208 synergized with platinum and paclitaxel across multiple ovarian cancer models, enhancing apoptosis and suppressing proliferation, clonogenicity, and invasion. Mechanistically, combination treatment increased DNA damage and amplified ER stress and apoptotic signaling. Importantly, ERX-208–based combinations showed enhanced antitumor activity in patient-derived explant, and xenograft models. These findings support a model in which ERX-208 impairs DNA damage response pathways and sensitizes ovarian cancer cells to DNA-damaging chemotherapy. Collectively, these findings provide a strong rationale for the combination strategy in clinical translation.
Significance:: This study demonstrates the clinical utility of ERX-208 in enhancing chemotherapy efficacy in ovarian cancer. By inducing sustained ER stress and a functional DNA repair–deficient state, ERX-208 sensitizes treatment-naïve and treatment-resistant tumors to platinum and taxanes. Findings support the rapid clinical development of ERX-class combinations, offering a rationale for pairing with standard regimens. This strategy may enable dose reduction, overcome resistance, expand options, and support biomarker-guided patient selection.
Related
- SPRY1 suppresses microglial fatty acid oxidation by retaining FATP3 on the endoplasmic reticulum in Alzheimer's disease.
- PRKACA modulates endoplasmic reticulum stress-associated dysfunction in granulosa cell models relevant to polycystic ovary syndrome
- Polycystin-2 functions as a calcium leak channel under endoplasmic reticulum stress to protect against myocardial ischemia
- Peripheral Axons Form Endoplasmic Reticulum-Rich Conduits With Breast Cancer Cells
- Endoplasmic reticulum and Golgi stress signaling-mediated regulation of protein secretion
BibTeX
@article{panneerdoss2026erx208,
title = {{ERX-208 Induces Endoplasmic Reticulum Stress and Suppresses DNA Damage Repair to Enhance Chemotherapy Sensitivity}},
author = {Durga Meenakshi Panneerdoss and Khaled Mohamed Nassar and Baskaran Subramani and William Cole Arnold and Sai Pranathi Vedagiri Venkata and Joe Hernandez and Behnam Ebrahimi and Sonal R. Chaudhari and Gaurav Sharma and Tae-Kyung Lee and Scott Elmore and Henry Neal and Uday P. Pratap and Gangadhara R. Sareddy and Edward R. Kost and Jung-Mo Ahn and Ganesh V. Raj and Ratna K. Vadlamudi},
journal = {Cancer Research Communications},
year = {2026},
month = oct,
doi = {10.1158/2767-9764.crc-26-0421},
url = {https://doi.org/10.1158/2767-9764.crc-26-0421},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - ERX-208 Induces Endoplasmic Reticulum Stress and Suppresses DNA Damage Repair to Enhance Chemotherapy Sensitivity
AU - Durga Meenakshi Panneerdoss
AU - Khaled Mohamed Nassar
AU - Baskaran Subramani
AU - William Cole Arnold
AU - Sai Pranathi Vedagiri Venkata
AU - Joe Hernandez
AU - Behnam Ebrahimi
AU - Sonal R. Chaudhari
AU - Gaurav Sharma
AU - Tae-Kyung Lee
AU - Scott Elmore
AU - Henry Neal
AU - Uday P. Pratap
AU - Gangadhara R. Sareddy
AU - Edward R. Kost
AU - Jung-Mo Ahn
AU - Ganesh V. Raj
AU - Ratna K. Vadlamudi
PY - 2026
DA - 2026/10/29
JO - Cancer Research Communications
DO - 10.1158/2767-9764.crc-26-0421
UR - https://doi.org/10.1158/2767-9764.crc-26-0421
AB - Ovarian cancer remains the most lethal gynecologic malignancy, driven in part by intrinsic and acquired therapeutic resistance to DNA-damaging chemotherapies. We previously demonstrated that ERX-208 targets the protein encoded by lysosomal acid lipase to induce catastrophic endoplasmic reticulum (ER) stress in ovarian cancer models. As ERX-class compounds advance to clinical development, rational combination strategies are needed to maximize therapeutic efficacy. To address this question, we conducted an unbiased in vitro screen of the combination of ERX-208 with 147 FDA-approved agents. We identified that DNA-damaging chemotherapies, including anthracyclines, oxaliplatin, and paclitaxel, were most synergistic in combination with ERX-208. Reanalysis of our transcriptomic data in ovarian cancer cells revealed coordinated suppression of DNA damage repair, DNA replication, and checkpoint pathways following ERX-208 treatment. Together, these data support a narrative that ERX-208 may selectively suppress DNA repair pathways and potentiate cytotoxicity by DNA-damaging agents. To test this hypothesis, we used platinum and paclitaxel, two standard-of-care agents in ovarian cancer. We found that ERX-208 synergized with platinum and paclitaxel across multiple ovarian cancer models, enhancing apoptosis and suppressing proliferation, clonogenicity, and invasion. Mechanistically, combination treatment increased DNA damage and amplified ER stress and apoptotic signaling. Importantly, ERX-208–based combinations showed enhanced antitumor activity in patient-derived explant, and xenograft models. These findings support a model in which ERX-208 impairs DNA damage response pathways and sensitizes ovarian cancer cells to DNA-damaging chemotherapy. Collectively, these findings provide a strong rationale for the combination strategy in clinical translation. Significance:: This study demonstrates the clinical utility of ERX-208 in enhancing chemotherapy efficacy in ovarian cancer. By inducing sustained ER stress and a functional DNA repair–deficient state, ERX-208 sensitizes treatment-naïve and treatment-resistant tumors to platinum and taxanes. Findings support the rapid clinical development of ERX-class combinations, offering a rationale for pairing with standard regimens. This strategy may enable dose reduction, overcome resistance, expand options, and support biomarker-guided patient selection.
SN - 2767-9764
ER -