Ribonucleotide Reductase in Hepatoblastoma Progression and Drug Resistance

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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.