Abstract Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of breast cancer, defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and low or absent human epidermal growth factor receptor 2 (HER2) expression. The lack of these therapeutic targets limits treatment options and contributes to poor clinical outcomes. Tyrosine kinase inhibitors (TKIs) offer a targeted approach by disrupting receptor tyrosine kinase (RTK) signaling pathways that drive tumor growth and survival. However, the emergence of resistance, mediated by compensatory signaling, genetic alterations, and epithelial-to-mesenchymal transition (EMT), remains a major barrier to sustained therapeutic efficacy. In this study, we hypothesized that chronic exposure to TKIs induces transcriptional reprogramming in epithelial TNBC cells, promoting drug resistance. Using RNA sequencing, we profiled differentially expressed genes (DEGs) in control and lapatinib-resistant MDA-MB-468 cells, an EGFR/HER2-driven TNBC model. We identified 129 DEGs and validated five of the most significantly modulated genes by qPCR and Western blotting. These genes were also associated with relapse-free survival in basal-like breast cancer patients. Notably, RAC2, a small Rho GTPase, emerged as a top candidate, showing robust upregulation in resistant cells. Compared to similar small GTPases, we found that this upregulation is specific to RAC2. RAC2 expression was found to be heterogeneous across TNBC cell lines and patient-derived xenograft (PDX) models, suggesting cell type-specific regulation. Ectopic overexpression of RAC2 in MDA-MB-468 cells conferred increased viability following treatment with lapatinib and neratinib and supported the resistance of TNBC cells to neratinib significantly. Furthermore, RAC2 upregulation significantly enhanced migratory and invasive behavior, as demonstrated by Transwell migration and Matrigel invasion assays. Our findings implicate RAC2 as a novel mediator of TKI resistance in TNBC and support its potential as a therapeutic target to restore drug sensitivity in resistant TNBC cells. Citation Format: Antonisha R. McIntosh, Ngoc Voung, Destiny Ball, Perrin Black, Alayjha Edwards, Qingguo Wang, Amos M. Sakwe. RAC2 as a mediator of drug resistance in triple-negative breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1793.
McIntosh et al. (Fri,) studied this question.