ERX 208 induces endoplasmic reticulum stress and suppresses DNA damage repair to enhance chemotherapy sensitivity

Abstract Ovarian cancer (OCa) remains the most lethal gynecologic malignancy, driven in part by intrinsic and acquired therapeutic resistance to DNA damaging chemotherapies. We previously identified that ERX-208 targets the protein encoded by Lysosomal acid lipase (LIPA) to induce catastrophic endoplasmic reticulum (ER) stress in OCa 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, antitumor antibiotics, oxaliplatin, and paclitaxel were most synergistic in combination with ERX-208. Reanalysis of our transcriptomic data in OCa cells revealed coordinated suppression of DNA damage repair (DDR), DNA replication, and checkpoint pathways following ERX-208 treatment. Together, these data support a narrative that ERX-208 may selectively suppress DDR pathways and potentiate cytotoxicity by DNA-damaging agents. To test this hypothesis, we used platinum, and paclitaxel, two standard-of-care agents in OCa. We noted that ERX-208 synergized with platinum and paclitaxel across multiple OCa 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 organoid, explant, and xenograft models, including therapy-resistant tumors. These findings support a model in which ERX-208 impairs DNA damage response pathways and sensitizes OCa cells to DNA-damaging chemotherapy. Collectively, these data provide a strong rationale for the combination strategy in clinical translation.