Abstract 6879: Inhibition of triple-negative breast cancer progression via ribosomal protein(s) modulation

Abstract Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with distinct features at the pathological, molecular and clinical levels that are associated with lower survival rates than other subtypes of breast cancer (BC). TNBC is a highly aggressive subtype of breast cancer and represents for 15-20% of all breast cancer cases. TNBC cancers present myriad clinical challenges due to their heterogeneity, poor prognosis, high recurrence, and high incidence of metastasis. Dysregulation of protein translation is a frequent feature of cancer. Translation of mRNAs to proteins i.e., protein synthesis via ribosomes, is a fundamental cellular activity. Increased levels of translation, necessary to support rapid cell proliferation, have been reported across different cancer types including TNBC. Methods: Cell viability and clonogenic assays were performed on a range of TNBC cells, including MDA-MB-231, MDA-MB-468, SUM159, HCC1395, HCC1806, EMT6, and 4T1. Cell cycle distribution was assessed through flow cytometry. LC-MS/MS analysis was performed on TMT-labeled samples for global proteome profiling. CETSA assay was performed to identify the target of CET019. The efficacy of CET019 (30 mg/kg) was tested using tumor (mouse and human cells) and patient derived xenograft studies. Results: Our studies show CET019 suppresses the clonogenic potential and growth of various triple-negative breast cancer cells. The CET019 treatment causes cell cycle arrest in TNBC cells at the G2/M phase. Proteomics analysis suggests that CET019 specifically affects the protein translation associated pathways. CETSA assay identified the thermal shift of various translation associated proteins, including RPLs and RPS. In vivo studies with CET019 found an inhibition of tumor growth kinetics in the mouse xenograft study with different TNBC models, as compared to the control group. We also observed that CET019 inhibited metastatic lung nodules. The results were further substantiated in four Patient Derived Xenograft (PDX) models. Conclusion: In summary, our study has strong preclinical evidence of CET019 as a promising lead candidate for TNBC treatment. “The complete chemical structures of the compounds used will be disclosed at the time of presentation at the meeting.” Citation Format: Arpit Dheeraj, Fernando Jose Marques, Dhanir Tailor, Abel Bermudez, Praveen Kumar, Benedikt Grau, Carrsyn B. Haley, Sharon Pitteri, Sanjay V. Malhotra. Inhibition of triple-negative breast cancer progression via ribosomal protein(s) modulation [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 6879.