Abstract 226: Effect of MCL-1 inhibitor on organoids derived from cholangiocarcinoma patients with IDH1 mutation

Abstract

Abstract Cholangiocarcinomas are highly aggressive malignancies with a poor prognosis. The global incidence of cholangiocarcinoma patients appears to be on the rise. While surgical resection remains the curative option for cholangiocarcinoma patients, the majority of cases are diagnosed at an advanced stage, resulting in poor outcomes. Patients with inoperable cholangiocarcinomas typically undergo chemotherapy regimens, including Gemcitabine, but their efficacy is limited, leading to low 5-year survival rates. Recent advancements in organoid culture technology allow for the in vitro replication of tissue structures by culturing tissue stem cells in three dimensions, offering great promise for personalized medicine. Utilizing patient-derived organoids has proven effective in predicting the outcomes of therapeutic drugs. We have successfully established organoids using cancer tissue derived from cholangiocarcinoma patients, and stably culturing and maintaining them, promoting their application to personalized medicine (Saito Y et al. Cell Rep. 27, 1265, 2019, Saito Y et al. Cancer Cell 40, 226, 2022). IDH1 mutations have been identified in approximately 15% of intrahepatic cholangiocarcinomas and are known to convert α-ketoglutarate (α-KG) in the TCA cycle to produce 2-hydroxyglutarate (2-HG), which is observed in gliomas and acute myeloid leukemia. 2-HG acts as an antagonist to α-KG-dependent dioxygenases, promoting cancer development. This study aims to develop a novel treatment for cholangiocarcinomas with IDH1 mutations. Metabolomic analysis of patient-derived cholangiocarcinoma organoids revealed 2-HG accumulation and reduced ATP production in IDH1-mutated cholangiocarcinoma organoids compared to IDH1 wild-type cholangiocarcinoma organoids. This may suppress the protein synthesis of MCL-1 and mTOR signaling through the activation of AMPK kinase, suggesting that further inhibition of MCL-1 could be lethal in IDH1-mutated cholangiocarcinoma organoids. Indeed, exposure to S63845, an MCL-1 inhibitor, significantly inhibited cell proliferation in IDH1-mutated cholangiocarcinoma organoids, unlike in IDH1 wild-type cholangiocarcinoma organoids. Furthermore, the combination of MCL-1 inhibitor and BCL-XL inhibitor demonstrated a synergistic and potent growth inhibitory effect on cholangiocarcinoma organoids. These findings indicate that the MCL-1 inhibitor holds promise as a new therapeutic agent for cholangiocarcinoma patients with IDH1 mutations. Citation Format: Shiho Suzuki, Juntaro Matsuzaki, Toshihide Muramatsu, Yae Kanai, Yoshimasa Saito. Effect of MCL-1 inhibitor on organoids derived from cholangiocarcinoma patients with IDH1 mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 226.