A Novel Approach to Classifying Chemotherapeutic Agents Based on Their Impact on Canonical Pathways: Implications for Overcoming Multidrug Resistance in Breast Cancer

Introduction: Breast cancer faces a significant challenge in the form of multidrug resistance (MDR), which requires the development of innovative therapeutic approaches. This study investigates the molecular mechanisms underlying MDR in MCF7 breast cancer cells to identify common signaling pathways that contribute to resistance. Additionally, this research aims to propose a novel classification system for chemotherapeutic agents based on their influence on these pathways. Methodology: To create drug-resistant MCF7 sublines, MCF7 cells were subjected to chemotherapeutic drugs for 12 months, with concentrations gradually increasing over time. The transcriptome of these sublines was then analyzed using next-generation RNA sequencing through Ion Torrent technology. Differentially expressed genes (DEGs) and their associated canonical pathways, molecular functions, and upstream regulators were identified using Ingenuity Pathway Analysis (IPA). Results: Unique mRNA expression patterns were associated with chemoresistance, indicating notable up- and downregulation patterns of DEGs in MCF7 chemoresistant subline cells. The use of IPA allowed for the categorization of chemotherapeutic drugs into three groups based on their effects on canonical pathways: Group I (Arabinosylcytosine, Methotrexate), Group II (Paclitaxel, Cyclophosphamide, Nocodazole), and Group III (5-Fluorouracil, Etoposide, Doxorubicin, Cisplatin). Conclusion: A new approach to enhance the effectiveness of breast cancer chemotherapy is proposed. This approach involves categorizing chemotherapeutic agents based on their impact on canonical pathways. The innovative classification system has the potential to guide the development of combination therapies, predict drug resistance mechanisms, and ultimately improve patient outcomes. However, it is essential to conduct extensive research and validate these findings in other breast cancer cell lines and clinical settings.