Abstract 5560: Exploring the role of Wnt, NFκb, and PI3 kinase pathways in oxaliplatin-resistant triple-negative breast carcinoma cell line

Breast cancer (BCa) is one of the major causes of mortality and morbidity in women globally. Triple negative breast cancer (TNBC) is known for its aggressive nature and is associated with high recurrence and metastasis with poor overall survival; 50% of the patients relapse in the first three years. Development of metastasis and drug resistance impacts survival in TNBC patients. The reasons for drug resistance and metastasis are complex and involve dysregulation of different cell signaling pathways, such as Wnt/β-catenin, NFκB and PI3K/AKT. Clinical studies have shown a favorable response to combination therapy using oxaliplatin in the treatment of metastatic breast cancer. This study explored the role of Wnt/β-catenin, NFκB and PI3K/AKT survival pathways in oxaliplatin-resistant TNBC cell line in vitro. Oxaliplatin-resistant clones were developed in the TNBC cell line MDA-MB-231 through sequential treatment with increasing doses of oxaliplatin. Differential gene expressions between chemoresistant clones and parental cells revealed the dysregulation of resistance-related genes, such as at 4µM treatment CD44 (p< 0.001), COX-2 (p < 0.001), ABCG2, BCL-2 (p < 0.05) and BAX (p < 0.01), alongside a shift towards a mesenchymal phenotype in resistant clones. Signaling pathways were altered, such as the upregulation of β-catenin in the Wnt/β-catenin pathway, Rel-A and NFκB1 in the NFκB pathway, and differential expression of AKT1, PIK3CA and mTOR1 in the PI3K/Akt pathway. Additionally, resistant clones displayed G2/M cell cycle arrest. The findings of the study enhance the understanding of drug resistance mechanisms in triple-negative breast cancer (TNBC) and identify possible targets for therapy. Citation Format: Asif Ahmad, Sheerien Rajput, Areeb Ahmed, Kulsoom Ghias, Azhar Hussain Rajabali. Exploring the role of Wnt, NFκb, and PI3 kinase pathways in oxaliplatin-resistant triple-negative breast carcinoma cell line [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 5560.