Abstract Chromosome 8 (chr8) gain, particularly the gain of its long arm 8q, represents one of the most frequent chromosomal abnormalities across multiple human cancers. In Ewing sarcoma, approximately 50% of cases exhibit chr8 gain while in prostate cancer, high level amplification of 8q occurs in about 24% of primary cases with much higher frequencies in metastatic cases. Across both diseases, the cohesin subunit gene RAD21, located on 8q24.11 region, has emerged as a key driver that facilitates chr8 gain by alleviating replication stress associated with oncogene activation. RAD21 is a highly conserved protein essential for establishing sister chromatid cohesin, chromatin looping, DNA replication, transcriptional regulation, and DNA damage repair. Our recent study demonstrated that elevated RAD21 expression correlates with increased cancer-specific mortality in prostate cancer, underscoring its potential role in tumor progression. However, how RAD21 mitigates replication-stress-associated DNA damage and modulates therapeutic response remains poorly understood. To address this gap, we investigated RAD21’s role in the DNA damage response (DDR) and treatment resistance using Ewing sarcoma and prostate cancer cell models. Using TurboID-based protein proximity labeling and mass spectrometry, we have demonstrated that RAD21 interacts with several key DNA damage initiating factors upon oncogenic induction including PARP1 and MRE11, suggesting that RAD21 engages with DNA repair initiating and homologous recombination (HR)-associated machinery. Given the clinical use of DNA damage-inducing PARP inhibitors (PARPi) for targeting HR-deficient cancers, we evaluated FDA-approved PARPi in isogenic Ewing sarcoma and prostate cancer cell models engineered to express distinct levels of RAD21. Our data showed that RAD21 overexpression markedly altered the cellular response to PARP inhibition in both models and this effect appears to be independent from cell-cycle regulation, consistent with a potential role for RAD21 enhancing HR-mediated DNA repair. In summary, our findings reveal an often overlooked function of RAD21 in altering DNA repair and influencing the response to therapeutic drugs targeting DNA repair pathways. Dysregulation of cohesin could contribute to therapeutic resistance and a potential biomarker for stratifying patients for DDR-targeted treatments. Citation Format: Chloe Springer, Elise DeArment, Ruoxi W. Wang, Thomas Janas, Xiaofeng A. Su. Effects of aneuploidy associated RAD21 gain on therapeutic response to PARP inhibition in Ewing sarcoma and prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 377.
Springer et al. (Fri,) studied this question.