Abstract LB159: Deregulation of CTC-associated RPL/RPS protein expression inhibits melanoma brain metastasis

Abstract

Abstract Melanoma brain metastasis (MBM) is associated with poor prognosis and low survival rates. MBM is diagnosed clinically in up to 60% of melanoma patients and in up to 80% of patients at autopsy. Circulating Tumor Cells (CTCs) are “seeds” of fatal metastasis and the smallest functional units of cancer. Our previous studies have employed a multilevel approach to identify a common CTC signature for ribosomal protein large/small subunits (RPL/RPS) which is linked to MBM development and progression1. Here, we hypothesized that targeting ribosomal biogenesis prevents MBM onset in CTC-derived xenografts. First, we treated CTC-injected MBM mice with RPL15 inhibitor omacetaxine to monitor metastatic progression. Second, parallel cohorts of mice were treated with CDK4/CDK6 inhibitor palbociclib with or without omacetaxine to assess effects of cell proliferation. Total flux of MBM signal was measured by IVIS and found to be higher in untreated mice. Mouse necropsies revealed decreased levels of MBM, along with metastatic dissemination to other organs. Third, collected mouse blood was analyzed by the FDA-approved ParsortixTM platform to enumerate CTC/CTC clusters (IHC), and evaluate their gene expression (RNA-seq). Lastly, metabolic profiling of inhibitor-treated versus untreated MBM CTC-derived clones was performed in vitro. Collectively, our findings indicate that the deregulation of ribosomal proteins inhibits MBM progression. This implicates a specific vulnerability of aggressive CTC subsets with high RPL/RPS content in MBM patients. RPL/RPS genetic screening could be a prognostic indicator of MBM severity and clinical outcomes. Our work promotes the concept that therapies targeting RPL/RPS proteins merit exploration as potential suppressors of metastatic progression in general, MBM in particular. 1. Bowley T, Lagutina I, Francis C, Sivakumar S, Selwyn R, Taylor E, et al. The RPL/RPS gene signature of melanoma updates CTCs associates with brain metastasis. Cancer Research Communications 2022;2: 1445-57. Citation Format: Tetiana Yuriyivna Bowley, Seth Merkley, Irina Lagutina, Dario Marchetti. Deregulation of CTC-associated RPL/RPS protein expression inhibits melanoma brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB159.