Abstract 933: Single-cell inference and validation of heterogeneous drug sensitivity in cholangiocarcinoma reveals dacinostat as novel therapeutic candidate

Abstract

Abstract Cholangiocarcinoma is a rare, aggressive malignancy with limited treatment options, due to a paucity of actionable mutations and low response to immune checkpoint inhibitors. Furthermore, its extreme heterogeneity prevents identification of actionable dependencies from bulk-tissue profiles, such that transformed cells themselves represent as little as 10% of cells comprising the complex micro-environment of these tumors. To address these challenges, we introduce a highly generalizable, single-cell framework for the mechanism-based prioritization of drugs to treat rare, heterogeneous tumors. Analysis of tumor cells isolated by single-cell RNA-Sequencing across six patients and two independent data sources using protein activity inference has revealed three molecularly distinct subphenotypes of cholangiocarcinoma cells, present to varying degrees across patients but with highly conserved proteomic signatures, and predicted to be sensitive to four drugs by regulatory network analysis. A seventh independent patient recapitulated these phenotypes, and drug sensitivity predictions at single-cell level for this patient were validated in low-passage, patient-derived xenografts from the same patient, which confirmed tumor growth rate control by two of these drugs (plicamycin and dacinostat) and further validated predicted subpopulation-specific effects, such that dacinostat alone inhibited tumor growth across all three tumor subphenotypes, while plicamycin preferentially inhibited some but not all, allowing the remaining phenotypes to reconstitute a treatment-resistant tumor. This approach suggests dacinostat as a promising candidate for follow-up clinical trials in cholangiocarcinoma, either alone or in combination with current standard-of-care chemotherapies, and is highly generalizable to elucidate complementary dependencies of other aggressive, heterogeneous tumors. Citation Format: Aleksandar Obradovic, Lorenzo Tomassoni, Daoqi Yu, Charles G. Drake, FIlemon Dela Cruz, Andrew Kung, Andrea Califano. Single-cell inference and validation of heterogeneous drug sensitivity in cholangiocarcinoma reveals dacinostat as novel therapeutic candidate [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 933.