# Ribonucleotide Reductase in Hepatoblastoma Progression and Drug Resistance

> **NIH NIH R21** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $246,714

## Abstract

PROJECT SUMMARY
Hepatoblastoma (HB) is a rare liver cancer that occurs exclusively in young children. Although most HB
tumors can be removed by surgery after chemotherapy, a small number of HB patients do develop recurrent
or metastatic disease following standard treatment and their survival is poor. Since clinical trials are limited
due to the rareness of this cancer, basic research is needed to understand the biology responsible for HB
progression and drug resistance in order to develop more effective treatment. Our recent study found
ribonucleotide reductase (RNR), an enzymatic complex catalyzing the formation of deoxyribonucleotides for
DNA replication and repair, is significantly upregulated in high-risk HB. The active RNR complex is a
heterodimeric tetramer constructed by a large RNR1 subunit and one of the two small RNR2 subunits, RRM2
or RRM2B. RRM2 is the dominant RNR2 subunit in dividing cells and is associated with the prognosis of
many solid tumors in adults. RRM2B is expressed low in cancer cells in general but can be induced under
stressful conditions. Our preliminary study showed that RRM2 knockdown significantly inhibited HB cell
growth, and more interestingly, treating HB cells with standard chemotherapy induced a significant
upregulation of RRM2B. In patient tumors removed after chemotherapy, there was also a much higher level of
RRM2B in the high-risk tumors compared to the low-risk tumors. Thus, we hypothesize that the subunit
switching from RRM2 to RRM2B during chemotherapy is a key mechanism through which HB cells retain
RNR activity to promote drug resistance. Therefore, RNR can be a potential therapeutic target for high-risk
and refractory HB. We propose to test this hypothesis by examining the switching and specific function of
RRM2 and RRM2B in HB progression and drug resistance, testing the efficacy of existing RRM2 inhibitors in
combination with chemotherapy in vitro and in vivo, and use a high-throughput approach to screen drugs that
can effectively degrade RRM2B in HB cells. The success of this project will unfold the dynamics of RNR
complex during HB development and adaption to chemotherapy, and provide scientific evidence supporting
RNR as a new therapeutic target for high-risk and refractory HB.

## Key facts

- **NIH application ID:** 10320059
- **Project number:** 5R21CA256464-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Liqin Zhu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $246,714
- **Award type:** 5
- **Project period:** 2021-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320059

## Citation

> US National Institutes of Health, RePORTER application 10320059, Ribonucleotide Reductase in Hepatoblastoma Progression and Drug Resistance (5R21CA256464-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320059. Licensed CC0.

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