2. Academic Validation
  3. Novel dual inhibitors of PARP and HDAC induce intratumoral STING-mediated antitumor immunity in triple-negative breast cancer

Novel dual inhibitors of PARP and HDAC induce intratumoral STING-mediated antitumor immunity in triple-negative breast cancer

  • Cell Death Dis. 2024 Jan 5;15(1):10. doi: 10.1038/s41419-023-06303-z.
Qingyun Zhu # 1 2,  Qiuzi Dai # 3 4,  Lei Zhao 2,  Chang Zheng 5,  Qinyuan Li 3,  Zigao Yuan 3,  Lulu Li 3,  Zhuoye Xie 3,  Zixuan Qiu 6,  Wenjun Huang 2,  Guowen Liu 5,  Xuyu Zu 7,  Bizhu Chu 8,  Yuyang Jiang 9 10 11 12
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China.
  • 2 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China.
  • 3 State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China.
  • 4 Academics Working Station, Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, 410219, China.
  • 5 Department of Breast and Thyroid Surgery, Second People's Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China.
  • 6 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
  • 7 The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China. zuxuyu0108@hotmail.com.
  • 8 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China. chubz@szu.edu.cn.
  • 9 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China. jiangyy@sz.tsinghua.edu.cn.
  • 10 State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China. jiangyy@sz.tsinghua.edu.cn.
  • 11 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China. jiangyy@sz.tsinghua.edu.cn.
  • 12 School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. jiangyy@sz.tsinghua.edu.cn.
  • # Contributed equally.
PMID: 38182579 DOI: 10.1038/s41419-023-06303-z
Abstract

PARP inhibitors and HDAC inhibitors have been approved for the clinical treatment of malignancies, but acquired resistance of or limited effects on solid tumors with a single agent remain as challenges. Bioinformatics analyses and a combination of experiments had demonstrated the synergistic effects of PARP and HDAC inhibitors in triple-negative breast Cancer. A series of novel dual PARP and HDAC inhibitors were rationally designed and synthesized, and these molecules exhibited high Enzyme inhibition activity with excellent antitumor effects in vitro and in vivo. Mechanistically, dual PARP and HDAC inhibitors induced BRCAness to restore synthetic lethality and promoted cytosolic DNA accumulation, which further activates the cGAS-STING pathway and produces proinflammatory chemokines through type I IFN-mediated JAK-STAT pathway. Moreover, these inhibitors promoted neoantigen generation, upregulated antigen presentation genes and PD-L1, and enhanced antitumor immunity when combined with Immune Checkpoint blockade therapy. These results indicated that novel dual PARP and HDAC inhibitors have antitumor immunomodulatory functions in triple-negative breast Cancer. Novel dual PARP and HDAC inhibitors induce BRCAness to restore synthetic lethality, activating tumoral IFN signaling via the cGAS-STING pathway and inducing cytokine production, promoting neoantigen generation and presentation to enhance the immune response.

Figures
Products