Applicability of Anticancer Drugs for the Triple-Negative Breast Cancer Based on Homologous Recombination Repair Deficiency.

Gaoming Liao,Xia Li,Yiran Yang,Jiali Zhu,Yunpeng Zhang,Jing Hu,Min Yan,Yun Xiao,Yao Zhou,Aimin Xie,Jianlong Liao,Zedong Jiang

doi:10.3389/fcell.2022.845950

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.

Highlights

For triple-negative breast cancer (TNBC), a highly heterogeneous subtype of breast cancer, there have been few advances in its targeted treatment until now (Torre et al, 2015; Yin et al, 2020)
For DNA-dependent protein kinase (DNA-PK), which is involved in the DNA damage response (DDR) pathways including non-homologous end joining (NHEJ) and homologous recombination (HR) (Shrivastav et al, 2008; Mohiuddin and Kang, 2019), we found the DNA-PK inhibitor NU-7441 exhibiting more sensitivity in Triple-negative breast cancer (TNBC) patients with HRdeficiency (ΔpIC50 > 0, p = 0.0065; Figures 1B,D)
We performed an integrated pharmacogenomic analysis to establish the drug sensitivity prediction model based on the homologous recombination repair deficiency (HRD) in TNBC patients

Summary

Introduction

For triple-negative breast cancer (TNBC), a highly heterogeneous subtype of breast cancer, there have been few advances in its targeted treatment until now (Torre et al, 2015; Yin et al, 2020). Onethird of TNBC patients achieve pathologic complete response (pCR) and better survival after received standard-of-care treatment for ACT, while the remaining show progress, recurrence and eventually death (Joensuu and Gligorov, 2012; Hatzis et al, 2016). Large-scale human cancer cell lines resources contain information about the response of hundreds of drugs, serving as vital pre-clinical models for studying anti-cancer therapeutics and determinants of drug sensitivity (SeashoreLudlow et al, 2015; Haverty et al, 2016; Iorio et al, 2016). A ridge regression model (Geeleher et al, 2014) can capture the relationship between the molecular characteristics of cancer cell lines and drug response by analyzing dataset from the cancer genomics project. Studies of human cancer cell lines promoted the effectiveness and wide popularity of pre-clinical model techniques in drug discovery

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Conclusion