Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive disease with historically poor outcomes, primarily due to the lack of effective targeted therapies. Here, we established a drug sensitivity prediction model based on the homologous recombination deficiency (HRD) using 83 TNBC patients from TCGA. Through analyzing the effect of HRD status on response efficacy of anticancer drugs and elucidating its related mechanisms of action, we found rucaparib (PARP inhibitor) and doxorubicin (anthracycline) sensitive in HR-deficient patients, while paclitaxel sensitive in the HR-proficient. Further, we identified a HRD signature based on gene expression data and constructed a transcriptomic HRD score, for analyzing the functional association between anticancer drug perturbation and HRD. The results revealed that CHIR99021 (GSK3 inhibitor) and doxorubicin have similar expression perturbation patterns with HRD, and talazoparib (PARP inhibitor) could kill tumor cells by reversing the HRD activity. Genomic characteristics indicated that doxorubicin inhibited tumor cells growth by hindering the process of DNA damage repair, while the resistance of cisplatin was related to the activation of angiogenesis and epithelial-mesenchymal transition. The negative correlation of HRD signature score could interpret the association of doxorubicin pIC50 with worse chemotherapy response and shorter survival of TNBC patients. In summary, these findings explain the applicability of anticancer drugs in TNBC and underscore the importance of HRD in promoting personalized treatment development.