Abstract 1223: A novel 3D high-throughput screen identified drugs that re-epithelialize colorectal cancer cells and enhance response to chemotherapy

Abstract Loss of polarity is a hallmark of cancer, and the related epithelial-to-mesenchymal transition (EMT) phenotype also impacts prognosis and therapy outcomes, particularly in colorectal cancer (CRC). However, the mechanisms and drugs that impact these morphologic changes are understudied, in part, due the complete failure of typical live/dead 2D high-throughput screens (HTS) to capture morphology or lack of robustness of 3D screens. Here, we designed an HTS using 3D type I collagen cultures of CRC cells to assess morphological changes in colonies and identified several FDA-approved drugs that re-epithelialize CRC colonies. One of these drugs, Azithromycin, increased colony circularity, enhanced E-cadherin membrane localization, and surprisingly, also elevated sensitivity to the chemotherapeutic, Irinotecan. A retrospective study of patient data demonstrated that the combination of Azithromycin with Irinotecan improved the 5-year survival of patients with CRC. These results highlight the importance of morphologic screens to identify novel drug candidates and synergistic mechanisms. Citation Format: Sarah J. Harmych, Thomas P. Hasaka, Chelsie K. Sievers, Seung W. Kang, Vivian T. Jones, Zhiguo Zhao, Oleg Kovtun, Claudia C. Wahoski, Ken S. Lau, Robert J. Coffey, Joshua A. Bauer, Bhuminder Singh. A novel 3D high-throughput screen identified drugs that re-epithelialize colorectal cancer cells and enhance response to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1223.