Single‐Cell Computational Frameworks for Quantifying BET Bromodomain Inhibitor Resistance and Screening Re‐Sensitizer Drugs in Triple‐Negative Breast Cancer

ABSTRACT Triple‐negative breast cancer (TNBC) is an aggressive subtype characterized by rapid proliferation and a great propensity for metastasis. Therapeutic options for TNBC remain limited due to the absence of targetable hormone receptors. While BET bromodomain inhibitors (BBDIs) exhibit promising anticancer potential, the emergence of drug resistance presents a major challenge. Here, through leveraging single‐cell RNA sequencing (scRNA‐seq) data across continuous states of BBDI treatment in TNBC, this study conducts an extensive investigation into BBDI resistance, and develops two computational frameworks, FR20 and D‐FR20, to quantify BBDI resistance at single‐cell resolution and to screen potential BBDI re‐sensitizer drugs, respectively. The accuracy and scalability of FR20 are confirmed through rigorous evaluation in nine independent datasets. In addition, cellular dynamic changes and ferroptosis inhibition are revealed in the evolution of BBDI resistance. Experimental validation demonstrates that GPX 4 overexpression significantly reduces drug sensitivity in TNBC cells. Furthermore, in vitro and in vivo experiments validate the ability of the small molecule filgotinib, identified by D‐FR20, to re‐sensitize BBDI and effectively eliminate resistant TNBC cells. Collectively, this study provides two computational frameworks for predicting BBDI resistance and candidate re‐sensitizer, as well as demonstrates the roles of ferroptosis in BBDI resistance, offering a promising avenue for TNBC treatment.