Baker Stacey J, Cosenza Stephen C, Ramana Reddy M V, Premkumar Reddy E
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Oncotarget. 2019 Mar 8;10(20):1932-1942. doi: 10.18632/oncotarget.26735.
Aberrant signaling triggered by oncogenic or hyperactive RAS proteins contributes to the malignant phenotypes in a significant percentage of myeloid malignancies. Of these, juvenile myelomonocytic leukemia (JMML), an aggressive childhood cancer, is largely driven by mutations in genes and those that encode regulators of these proteins. The mouse model mirrors several key features of this disease and has been used extensively to determine the utility and mechanism of small molecule therapeutics in the context of RAS-driven myeloproliferative disorders. Treatment of disease-bearing KRAS mice with rigosertib (RGS), a small molecule RAS mimetic that is in phase II and III clinical trials for MDS and AML, decreased the severity of leukocytosis and splenomegaly and extended their survival. RGS also increased the frequency of HSCs and rebalanced the ratios of myeloid progenitors. Further analysis of KRAS HSPCs revealed that RGS suppressed hyperproliferation in response to GM-CSF and inhibited the phosphorylation of key RAS effectors. Together, these data suggest that RGS might be of clinical benefit in RAS-driven myeloid disorders.
致癌性或高活性RAS蛋白引发的异常信号传导在相当比例的髓系恶性肿瘤中导致恶性表型。其中，青少年粒单核细胞白血病（JMML）是一种侵袭性儿童癌症，很大程度上由基因以及编码这些蛋白调节因子的基因突变驱动。该小鼠模型反映了这种疾病的几个关键特征，并已被广泛用于确定小分子疗法在RAS驱动的骨髓增殖性疾病中的效用和机制。用瑞戈非尼（RGS）治疗携带疾病的KRAS小鼠，RGS是一种小分子RAS模拟物，正在进行MDS和AML的II期和III期临床试验，可降低白细胞增多症和脾肿大的严重程度并延长其生存期。RGS还增加了造血干细胞的频率并重新平衡了髓系祖细胞的比例。对KRAS造血干细胞的进一步分析表明，RGS抑制了对粒细胞-巨噬细胞集落刺激因子（GM-CSF）的过度增殖反应，并抑制了关键RAS效应器的磷酸化。这些数据共同表明，RGS可能对RAS驱动的髓系疾病具有临床益处。
