Abstract C088: Understanding the role of tumor suppressor gene <i>ARID1A</i> in gastric cancer development and therapeutic response

Abstract Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. While more recent incidence and mortality rates have dropped, GC remains a significant cause of health disparities for many underserved and under-resourced communities in the US, including racial and ethnic minorities. Despite a high minority cancer burden, few FDA-approved targeted therapies are available for GC. This can be partially explained by limited availability of cancer genomic data and patient-derived models from diverse populations, which hamper therapeutic target identification and drug efficacy studies. To address this, our group has spearheaded two patient-derived xenograft and organoid development and trial centers to generate and characterize preclinical models of GC that are representative of the patient population. Genomic sequencing of a Latino GC cohort revealed over 30% of tumors harbored pathogenic mutations in the tumor suppressor gene, ARID1A. This is comparable to frequencies observed in TCGA, suggesting that ARID1A may be a bona fide driver of GC. ARID1A functions within the SWI/SNF (BAF) chromatin remodeling complex to regulate chromatin accessibility. We performed Cut-and-Run and RNA-Seq to identify chromatin-mediated alterations in gene expression in Latino patient-derived organoids with ARID1A mutations vs those with wildtype ARID1A, and in normal gastric organoids that we engineered with ARID1A knockout mutations using CRISPR/Cas9 compared unedited normal gastric organoids. Analyses revealed significant alterations in multiple signaling pathways implicated in cancer proliferation and migration. To investigate sensitivity to inhibitors targeting altered pathways, we then performed drug response screens in these models with targeted inhibitors against PARP enzymes (PARPi) and PI3K/Akt (PI3Ki, AKTi) pathway. Results revealed varied vulnerability against individual targeted inhibitors, which we are actively testing in combination for greater efficacy. These studies address critical knowledge gaps in ARID1A-related tumor biology and may inform precision medicine approaches in an underserved and disproportionately affected population. Citation Format: Nicole Halmai, Jasmine Diaz, Alexa Morales Arana, Hongyong Zhang, Paul Lott, Ana Estrada-Florez, Luis Carvajal-Carmona. Understanding the role of tumor suppressor gene ARID1A in gastric cancer development and therapeutic response [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C088.