Utilization of Cancer Cell Line Screening to Elucidate the Anticancer Activity and Biological Pathways Related to the Ruthenium-Based Therapeutic BOLD-100

SIMPLE SUMMARY: There is an unmet need for novel anticancer therapeutics that work differently to current standard-of-care therapies. BOLD-100 is a unique clinical-stage anticancer compound that is based on the rare metal, ruthenium. Understanding the bioactivity of BOLD-100 can accelerate its development towards approval and into clinical practice. The aim of this study was to use a large panel of cancer cell lines to formulate a sensitivity profile of BOLD-100 across various cancer types. BOLD-100 demonstrated increased activity in cell lines from esophageal cancer, blood cancers, and bladder cancer. These indications are in addition to the gastrointestinal cancers currently in clinical development, thus opening new opportunities. Using the sensitivity profile for downstream bioinformatics and pathway analysis revealed associations between cancer cell lines’ sensitivity to BOLD-100 and ribosomal gene expression, including several genes coding for large- and small-ribosomal subunits. These findings provide evidence that ribosomal processes may be a critical component of BOLD-100’s mechanism. ABSTRACT: BOLD-100 (sodium trans-[tetrachlorobis(1H indazole)ruthenate(III)]) is a ruthenium-based anticancer compound currently in clinical development. The identification of cancer types that show increased sensitivity towards BOLD-100 can lead to improved developmental strategies. Sensitivity profiling can also identify mechanisms of action that are pertinent for the bioactivity of complex therapeutics. Sensitivity to BOLD-100 was measured in a 319-cancer-cell line panel spanning 24 tissues. BOLD-100’s sensitivity profile showed variation across the tissue lineages, including increased response in esophageal, bladder, and hematologic cancers. Multiple cancers, including esophageal, bile duct and colon cancer, had higher relative response to BOLD-100 than to cisplatin. Response to BOLD-100 showed only moderate correlation to anticancer compounds in the Genomics of Drug Sensitivity in Cancer (GDSC) database, as well as no clear theme in bioactivity of correlated hits, suggesting that BOLD-100 may have a differentiated therapeutic profile. The genomic modalities of cancer cell lines were modeled against the BOLD-100 sensitivity profile, which revealed that genes related to ribosomal processes were associated with sensitivity to BOLD-100. Machine learning modeling of the sensitivity profile to BOLD-100 and gene expression data provided moderative predictive value. These findings provide further mechanistic understanding around BOLD-100 and support its development for additional cancer types.