Fatkhutdinov Nail, Sproesser Katrin, Krepler Clemens, Liu Qin, Brafford Patricia A, Herlyn Meenhard, Aird Katherine M, Zhang Rugang
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania. Kazan Federal University, Kazan, Russia.
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Mol Cancer Res. 2016 Sep;14(9):767-75. doi: 10.1158/1541-7786.MCR-16-0099. Epub 2016 Jun 13.
The majority of patients with melanoma harbor mutations in the BRAF oncogene, thus making it a clinically relevant target. However, response to mutant BRAF inhibitors (BRAFi) is relatively short-lived with progression-free survival of only 6 to 7 months. Previously, we reported high expression of ribonucleotide reductase M2 (RRM2), which is rate-limiting for de novo dNTP synthesis, as a poor prognostic factor in patients with mutant BRAF melanoma. In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression and increased apoptotic markers. After discontinuing PLX4720 treatment, cells showed marked recurrence. However, knockdown of RRM2 attenuated this rebound growth both in vitro and in vivo, which correlated with maintenance of the senescence-associated cell-cycle arrest.
Inhibition of RRM2 converts the transient response of melanoma cells to BRAFi to a stable response and may be a novel combinatorial strategy to prolong therapeutic response of patients with melanoma. Mol Cancer Res; 14(9); 767-75. ©2016 AACR.
大多数黑色素瘤患者的BRAF癌基因存在突变，因此使其成为一个具有临床相关性的靶点。然而，对突变型BRAF抑制剂（BRAFi）的反应相对短暂，无进展生存期仅为6至7个月。此前，我们报道核糖核苷酸还原酶M2（RRM2）高表达是突变型BRAF黑色素瘤患者的不良预后因素，RRM2是从头合成脱氧核苷酸三磷酸（dNTP）的限速酶。在本研究中，探讨了通过敲低RRM2靶向从头合成dNTP能否延长黑色素瘤细胞对BRAFi反应的这一概念。与单独使用任何一种治疗方法相比，敲低RRM2并联合使用突变型BRAFi PLX4720（FDA批准药物维莫非尼的类似物）能更大程度地抑制黑色素瘤细胞增殖。这在多种突变型BRAF细胞系的体外实验以及一种新的患者来源异种移植（PDX）模型系统中均有发生。从机制上讲，联合使用增加了DNA损伤积累，这与DNA损伤修复（DDR）基因表达的整体下降以及凋亡标志物增加相关。停止PLX4720治疗后，细胞出现明显复发。然而，敲低RRM2在体外和体内均减弱了这种反弹生长，这与衰老相关的细胞周期停滞的维持相关。
抑制RRM2可将黑色素瘤细胞对BRAFi的短暂反应转变为稳定反应，可能是延长黑色素瘤患者治疗反应的一种新的联合策略。《分子癌症研究》；14(9)；767 - 75。©2016美国癌症研究协会。
