2. Academic Validation
  3. Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor

Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor

  • J Exp Clin Cancer Res. 2023 Dec 20;42(1):346. doi: 10.1186/s13046-023-02911-x.
Le Hien Giang 1 2,  Kuo-Sheng Wu 3,  Wei-Chung Lee 3 4,  Shing-Shung Chu 3,  Anh Duy Do 1 5,  Chun A Changou 4 6,  Huy Minh Tran 7,  Tsung-Han Hsieh 8,  Hsin-Hung Chen 9,  Chia-Ling Hsieh 4 10,  Shian-Ying Sung 1 4,  Alice L Yu 11 12,  Yun Yen 6,  Tai-Tong Wong 3 13 14 15 16,  Che-Chang Chang 17 18 19 20 21
Affiliations

Affiliations

  • 1 International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
  • 2 Department of Biology and Genetics, Hai Phong University of Medicine and Pharmacy, Hai Phong, 180000, Vietnam.
  • 3 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
  • 4 The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan.
  • 5 Department of Physiology, Pathophysiology and Immunology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, 700000, Vietnam.
  • 6 The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
  • 7 Department of Neurosurgery, Faculty of Medicine, University of Medicine and Pharmacy, Ho Chi Minh City, 700000, Vietnam.
  • 8 Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, 110, Taiwan.
  • 9 Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, 112, Taiwan.
  • 10 Laboratory of Translational Medicine, Development Center for Biotechnology, Taipei, 115, Taiwan.
  • 11 Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan, 333, Taiwan.
  • 12 Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.
  • 13 Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei, 110, Taiwan.
  • 14 Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei Medical University Hospital and Taipei Neuroscience Institute, Taipei Medical University, Taipei, 110, Taiwan.
  • 15 Neuroscience Research Center, Taipei Medical University Hospital, Taipei, 110, Taiwan.
  • 16 TMU Research Center for Cancer Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan.
  • 17 International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan. ccchang168@tmu.edu.tw.
  • 18 The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan. ccchang168@tmu.edu.tw.
  • 19 Neuroscience Research Center, Taipei Medical University Hospital, Taipei, 110, Taiwan. ccchang168@tmu.edu.tw.
  • 20 TMU Research Center for Cancer Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan. ccchang168@tmu.edu.tw.
  • 21 The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, 6F., Education & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., New Taipei City, 23564, Taiwan. ccchang168@tmu.edu.tw.
PMID: 38124207 DOI: 10.1186/s13046-023-02911-x
Abstract

Background: Atypical teratoid rhabdoid tumors (ATRT) is a rare but aggressive malignancy in the central nervous system, predominantly occurring in early childhood. Despite aggressive treatment, the prognosis of ATRT patients remains poor. RRM2, a subunit of ribonucleotide reductase, has been reported as a biomarker for aggressiveness and poor prognostic conditions in several cancers. However, little is known about the role of RRM2 in ATRT. Uncovering the role of RRM2 in ATRT will further promote the development of feasible strategies and effective drugs to treat ATRT.

Methods: Expression of RRM2 was evaluated by molecular profiling analysis and was confirmed by IHC in both ATRT patients and PDX tissues. Follow-up in vitro studies used shRNA knockdown RRM2 in three different ATRT cells to elucidate the oncogenic role of RRM2. The efficacy of COH29, an RRM2 inhibitor, was assessed in vitro and in vivo. Western blot and RNA-sequencing were used to determine the mechanisms of RRM2 transcriptional activation in ATRT.

Results: RRM2 was found to be significantly overexpressed in multiple independent ATRT clinical cohorts through comprehensive bioinformatics and clinical data analysis in this study. The expression level of RRM2 was strongly correlated with poor survival rates in patients. In addition, we employed shRNAs to silence RRM2, which led to significantly decrease in ATRT colony formation, cell proliferation, and migration. In vitro experiments showed that treatment with COH29 resulted in similar but more pronounced inhibitory effect. Therefore, ATRT orthotopic mouse model was utilized to validate this finding, and COH29 treatment showed significant tumor growth suppression and prolong overall survival. Moreover, we provide evidence that COH29 treatment led to genomic instability, suppressed homologous recombinant DNA damage repair, and subsequently induced ATRT cell death through Apoptosis in ATRT cells.

Conclusions: Collectively, our study uncovers the oncogenic functions of RRM2 in ATRT cell lines, and highlights the therapeutic potential of targeting RRM2 in ATRT. The promising effect of COH29 on ATRT suggests its potential suitability for clinical trials as a novel therapeutic approach for ATRT.

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