{
  "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.\n\nSignificance:: 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.",
    "Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas.",
    "Mays Cancer Center, San Antonio, Texas.",
    "EtiraRx, Dallas, Texas.",
    "Audie L. Murphy South Texas Veterans Health Care System, San Antonio, Texas."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Durga Meenakshi Panneerdoss",
      "orcid": "0009-0001-8162-5277"
    },
    {
      "affs": [
        0
      ],
      "name": "Khaled Mohamed Nassar",
      "orcid": "0000-0001-5510-2838"
    },
    {
      "affs": [
        0
      ],
      "name": "Baskaran Subramani",
      "orcid": "0000-0001-6966-3484"
    },
    {
      "affs": [
        0
      ],
      "name": "William Cole Arnold",
      "orcid": "0009-0001-0750-432X"
    },
    {
      "affs": [
        0
      ],
      "name": "Sai Pranathi Vedagiri Venkata",
      "orcid": "0009-0005-2468-2741"
    },
    {
      "affs": [
        0
      ],
      "name": "Joe Hernandez",
      "orcid": "0009-0000-8188-5928"
    },
    {
      "affs": [
        0
      ],
      "name": "Behnam Ebrahimi",
      "orcid": "0000-0003-4588-7525"
    },
    {
      "affs": [
        0
      ],
      "name": "Sonal R. Chaudhari",
      "orcid": "0000-0001-7505-1628"
    },
    {
      "affs": [
        0
      ],
      "name": "Gaurav Sharma",
      "orcid": "0000-0001-7377-0880"
    },
    {
      "affs": [
        1
      ],
      "name": "Tae-Kyung Lee",
      "orcid": "0000-0001-6305-2631"
    },
    {
      "affs": [
        1
      ],
      "name": "Scott Elmore",
      "orcid": "0009-0004-1782-5364"
    },
    {
      "affs": [
        1
      ],
      "name": "Henry Neal",
      "orcid": "0009-0004-6047-5347"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Uday P. Pratap",
      "orcid": "0000-0003-2973-0210"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Gangadhara R. Sareddy",
      "orcid": "0000-0001-9977-3932"
    },
    {
      "affs": [
        0
      ],
      "name": "Edward R. Kost",
      "orcid": "0000-0001-9613-1643"
    },
    {
      "affs": [
        1
      ],
      "name": "Jung-Mo Ahn",
      "orcid": "0000-0002-9104-525X"
    },
    {
      "affs": [
        3
      ],
      "name": "Ganesh V. Raj",
      "orcid": "0009-0003-3325-4808"
    },
    {
      "affs": [
        0,
        2,
        4
      ],
      "name": "Ratna K. Vadlamudi",
      "orcid": "0000-0003-2849-4076"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5tydmete778m4.bib",
  "cited_by": 0,
  "doi": "10.1158/2767-9764.crc-26-0421",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13718282/",
  "id": "5tydmete778m4",
  "issns": [
    "2767-9764"
  ],
  "landing_url": "https://doi.org/10.1158/2767-9764.crc-26-0421",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Chemotherapy"
    ],
    [
      "heading",
      "Gynecological Cancers"
    ],
    [
      "heading",
      "Ovarian Cancer"
    ],
    [
      "heading",
      "Research Article"
    ],
    [
      "heading",
      "Small Molecule Agents"
    ],
    [
      "openalex",
      "2743|Ovarian cancer diagnosis and treatment"
    ]
  ],
  "openalex": "W7220835597",
  "pdf_url": "https://aacrjournals.org/cancerrescommun/article-pdf/doi/10.1158/2767-9764.CRC-26-0421/3837247/crc-26-0421.pdf",
  "pmcid": "PMC13718282",
  "pmid": "42842296",
  "published": "2026-10-29",
  "publisher": "American Association for Cancer Research",
  "ris": "https://research.draconitic.com/paper/5tydmete778m4.ris",
  "sources": [
    {
      "first_seen": "2026-11-02T12:22:20Z",
      "native_id": "PMC13718282",
      "source": "pmc",
      "url": "https://doi.org/10.1158/2767-9764.crc-26-0421"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2743|Ovarian cancer diagnosis and treatment",
      "subfield": "reproductive-child"
    }
  ],
  "title": "ERX-208 Induces Endoplasmic Reticulum Stress and Suppresses DNA Damage Repair to Enhance Chemotherapy Sensitivity",
  "title_text": "ERX-208 Induces Endoplasmic Reticulum Stress and Suppresses DNA Damage Repair to Enhance Chemotherapy Sensitivity",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T12:22:20Z",
  "url": "https://research.draconitic.com/paper/5tydmete778m4",
  "venue": "Cancer Research Communications",
  "versions": []
}