Ribonucleotide reductase large subunit (RRM1) as a novel therapeutic target in multiple myeloma

Purpose: To investigate the biologic and clinical significance of ribonucleotide reductase (RR) in multiple myeloma (MM). <p>Experimental Design: We assessed the impact of RR expression on patient outcome in MM. We then characterized the effect of genetic and pharmacological inhibition of RRM1 on MM growth and survival using siRNA and clofarabine (CLO), respectively, both in vitro and in vivo mouse xenograft model.</p> <p>Results: Newly diagnosed MM patients with higher RRM1 expression have shortened survival. Knockdown of RRM1 triggered significant growth inhibition and apoptosis in MM cells, even in the context of the bone marrow microenvironment. Gene expression profiling showed upregulation of DNA damage response genes and p53 regulated genes after RRM1 knockdown. Immunoblot and QRT-PCR analysis confirmed that -H2A.X, ATM, ATR, Chk1, Chk2, RAD51, 53BP1, BRCA1, and BRCA2 were upregulated/activated. Moreover, immunoblots showed that p53, p21, Noxa, and Puma were activated in p53 wild-type MM cells. Clofarabine (CLO), a purine nucleoside analog that inhibits RRM1, induced growth arrest and apoptosis in p53 wild-type cell lines. Although CLO did not induce cell death in p53 mutant cells, it did trigger synergistic toxicity in combination with DNA damaging agent melphalan. Finally, we demonstrated that tumor growth of RRM1-knockdown MM cells was significantly reduced in a murine human MM cell xenograft model.</p> Conclusions: Our results therefore demonstrate that RRM1 is a novel therapeutic target in MM in preclinical setting, and provide the basis for clinical evaluation of RRM1 inhibitor, alone or in combination with DNA damaging agents, to improve patient outcome in MM.

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