16Functional Screening of ARID1A-Deficient Cholangiocarcinoma Using the MAPS Platform
Wenjia Wang, Olivia Schmidt, Sara K Blick-Nitko, Aslihan Ambeskovic, Diana Agostini-Vulaj, Hartmut K Land, Isaac S Harris, Aram F HezelAbstract
Background & Objectives
Cholangiocarcinoma (CCA) is an aggressive malignancy characterized by a high frequency of chromatin-remodeling gene alterations and has limited therapeutic options. Approximately 47% of intrahepatic CCA cases present alterations in at least one gene associated with chromatin remodeling with loss-of-function mutations in ARID1A occurring in ∼19-22% of cases. However, actionable vulnerabilities associated with ARID1A deficiency remain poorly defined. We hypothesized that ARID1A deficiency creates distinct, targetable cellular dependencies that can be systematically identified through functional screening.
Method
To test this hypothesis, we utilized the Multifunctional Approach to Pharmacologic Screening (MAPS) platform to perform comparative functional screens in murine cholangiocarcinoma cell lines derived from genetically engineered mouse models that are Arid1a-null or Arid1a-wildtype. This platform enables rapid, high-throughput assessment of cellular responses to pharmacologic perturbations across hundreds of molecular pathways. The MAPS libraries contain compounds arrayed across ten dilution points, allowing for a robust understanding of differential drug sensitivities. Further, MAPS allows us to focus on compounds with established in vivo profiles, including FDA-approved drugs and compounds with known safety data, thereby accelerating the path from discovery to clinical implementation.
Results
Screening results revealed distinct sensitivity patterns between Arid1a-null and Arid1a-wildtype cells, supporting the hypothesis that ARID1A loss alters pathway reliance in cholangiocarcinoma. Notably, Arid1a-null cells displayed enhanced sensitivity to perturbations impacting stress response pathways, including ferroptosis.
Conclusion
This study establishes a functional screening framework to identify therapeutic targets associated with ARID1A loss and provides a foundation for downstream validation and translational studies aimed at improving treatment strategies for ARID1A-mutant CCA.