Seipel Katja, Marques Miguel A T, Sidler Corinne, Mueller Beatrice U, Pabst Thomas
Department for Biomedical Research (DBMR), University of Bern, 3008 Bern, Switzerland.
Department of Medical Oncology, University Hospital Bern, 3010 Bern, Switzerland.
Cancers (Basel). 2018 May 31;10(6):170. doi: 10.3390/cancers10060170.
The tumor suppressor protein p53 is inactivated in a large variety of cancer cells. Cellular p53 inhibitors like the mouse double minute 2 homolog (MDM2) commonly suppress the p53 function in acute myeloid leukemia (AML). Moreover, fms like tyrosine kinase 3 (FLT3) growth factor signaling pathways including the mitogen-activated kinase (MAPK) cascade (RAS-RAF-MEK-ERK) are highly active in AML cells. Consequently, the combined administration of MDM2 and MEK inhibitors may present a promising anti-leukemic treatment strategy. Here we assessed the MDM2 antagonist idasanutlin and the MEK1 inhibitor cobimetinib as single agents and in combination in a variety of AML cell lines and primary AML blast cells for their ability to induce apoptosis and cell death. AML cell lines and blast cells comprised all major AML subtypes based on the mutational status of and genes. We observed a considerably varying anti-leukemic efficacy of idasanutlin and cobimetinib. AML cells with high sensitivity to the single compounds as well as to the combined treatment emerged with normal karyotype, wild-type and elevated FLT3 and MDM2 protein levels. Our data indicate that AML cells with normal karyotype (NK) and wild-type status of with elevated FLT3 and MDM2 expression emerge to be most sensitive to the combined treatment with cobimetinib and idasanutlin. FLT3 and MDM2 are biomarkers for treatment response to idasanutlin and cobimetinib in AML.
肿瘤抑制蛋白p53在多种癌细胞中失活。细胞内p53抑制剂，如小鼠双微体2同源物（MDM2），通常会抑制急性髓系白血病（AML）中的p53功能。此外，包括丝裂原活化蛋白激酶（MAPK）级联反应（RAS-RAF-MEK-ERK）在内的类fms酪氨酸激酶3（FLT3）生长因子信号通路在AML细胞中高度活跃。因此，联合使用MDM2和MEK抑制剂可能是一种有前景的抗白血病治疗策略。在此，我们评估了MDM2拮抗剂idasanutlin和MEK1抑制剂cobimetinib作为单一药物以及联合使用时，在多种AML细胞系和原发性AML原始细胞中诱导凋亡和细胞死亡的能力。AML细胞系和原始细胞涵盖了基于 和 基因的突变状态的所有主要AML亚型。我们观察到idasanutlin和cobimetinib的抗白血病疗效差异很大。对单一化合物以及联合治疗高度敏感的AML细胞出现了正常核型、野生型 以及FLT3和MDM2蛋白水平升高的情况。我们的数据表明，核型正常（NK）且 为野生型状态、FLT3和MDM2表达升高的AML细胞对cobimetinib和idasanutlin联合治疗最为敏感。FLT3和MDM2是AML中对idasanutlin和cobimetinib治疗反应的生物标志物。
