Abstract 466: Combinatorial screening reveals novel gene-drug synergies in breast cancer cells.

作者：Jifeng Wang, J Bauer, Jie Wu, Lili Xu, Regina Courtney, Guochong Damon Jia, Jirong Long, Wei Zheng, Qiuyin Cai · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-466 · 研究领域：Bioinformatics and Genomic Networks、Protein Degradation and Inhibitors、PARP inhibition in cancer therapy

Abstract Background: Breast cancer is the most common malignancy among women in the United States. It is a molecularly heterogeneous disease with diverse therapeutic responses. Our previous transcriptome-wide association (TWAS) and fine-mapping studies identified candidate genes potentially involved in breast cancer susceptibility. To advance personalized chemo-preventive and therapeutic strategies, we conducted a gene-drug synergy study on selected candidate susceptibility genes. Methods: Based on our previous multi-omics analyses, TWAS, and fine-mapping, we conducted a high-throughput siRNA screen to assess cell proliferation and prioritized 25 candidate genes for combinatorial screening. Using reverse transfection with ON-TARGETplus SMARTpool siRNAs (Dharmacon), these genes were silenced in three breast cancer cell lines (MCF-7, T47D, and MDA-MB-231). Following knockdown, cells were treated for 72 h with 18 clinically relevant agents for cancer therapy, including PARP inhibitors, CDK4/6 inhibitors, endocrine therapies, and chemotherapeutics, at clinically relevant concentrations. Cell viability and cytotoxicity were assessed by Hoechst 33342 and propidium iodide staining with automated image analysis. Gene-drug combinations showing >2-fold increase in cell death versus siRNA-silenced DMSO controls were considered synergistic. Statistical significance was determined using Student’s t-test. Results: This combinatorial screening approach revealed multiple gene-drug syn...