Abstract 6819: TOMM40/FADS2 expression ratio predicts the sensitivity to mTOR inhibitors in triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that does not express the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Because of the negative to ER, PR and HER2, the current targeted therapy is not fully working for TNBC. Deregulated mTOR signaling has been reported to have implications in several human diseases, including cancer. This study aimed to explore the prognostic significance of the mTORC1 gene set and identify potential biomarkers for predictive the therapeutic effectiveness of mTOR inhibitors on TNBC. Methods: The transcriptional profile of normal tissues and primary tumors derived from TNBC patients was obtained from The Cancer Genome Atlas (TCGA) database and used to generate the differentially expressed genes (DEGs) of mTORC1 gene set from Molecular Signatures Database. Cox regression analysis for the DEGs against overall survival of TNBC patients was employed to identify independent prognostic factors. The Chi-square test of independence was used to study the association among the identified prognostic genes and the clinicopathological characteristics of TNBC patients. RT-PCR, immunohistochemistry (IHC) staining and Western blot experiments were used to detect endogenous expression levels of the identified prognostic genes in a panel of TNBC cell lines. MTT assay were used to assess the sensitivity/resistance of TNBC cells to mTOR inhibitors. Results: Two potential prognostic genes FADS2 and TOMM40 were identified from 56 differentially expressed genes (DEGs) between normal tissues and primary tumors of TCGA TNBC patients. Where FADS2 is a protective factor (HR= 0.652), TOMM40 (HR= 2.243) serves as a risk factor under overall survival condition. The signature of TOMM40 downregulation and FADS2 upregulation was associated with a favorable overall survival; conversely the higher TOMM40/FADS2 ratio was referred to a poor outcome in TNBC patients. Under overall survival condition, the TOMM40/FADS2 ratio was shown to significantly (p < 0.05) associate with age, tumor size, lymph node metastasis, pathologic stage and overall survival event. Notably, cell-based cytotoxicity assay revealed that TNBC cells harboring a higher TOMM40/FADS2 ratio compared to TNBC cells with a lower TOMM40/FADS2 ratio are more sensitive to mTOR inhibitor treatment. Conclusion: Our results provide the expression ratio of TOMM40/FADS2 genes as a useful biomarker to predict the therapeutic efficacy of mTOR inhibitors in TNBC. Citation Format: Salman Mohamed Farah, Yuan-Feng Lin. TOMM40/FADS2 expression ratio predicts the sensitivity to mTOR inhibitors in triple-negative breast cancer [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 6819.