Abstract PS2-12-12: Targeting RNA binding protein-deficiency associated neoepitopes for triple negative breast cancers

Abstract Neoantigen-based cancer vaccines are largely individualized treatment modalities based on a patient’s DNA mutations. However, tumor-specific neoantigen formation may also come about as the result of other downstream processes like splicing dysregulation and nonsense mediated RNA decay (NMD) that result in aberrant transcripts. Such processes can be regulated by RNA binding proteins (RBPs). We have shown previously that one such RBP, hnRNPM, preferentially binds to UG-rich motifs and suppresses cryptic splice sites. Knockdown of hnRNPM resulted in consistent upregulation of common aberrant cryptic transcripts across multiple cancer cell lines. We identified a peptide produced by translation of these hnRNPM-associated cryptic transcripts in triple negative breast cancer cell lines. This peptide is predicted to be a strong binder to human leukocyte antigen class I (HLA-I) and does not map to canonical protein sequences. In addition, we have identified several other RBP candidates through analysis of public omics datasets of patient gene expression and clinical response to immunotherapy. These preliminary results will be followed up with further characterization of the neoantigens produced by RBP dysregulations. The goal will be to develop a pool of clinically actionable neoantigens for individual patients by searching for RBP dysregulations that can predictably produce abnormal neoantigens. Citation Format: M. Lee. Targeting RNA binding protein-deficiency associated neoepitopes for triple negative breast cancers [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-12-12.