Seipel Katja, Kopp Basil, Bacher Ulrike, Pabst Thomas
Department for Biomedical Research (DBMR), University of Berne, 3008 Bern, Switzerland.
Department of Medical Oncology, University Hospital Berne, 3010 Bern, Switzerland.
Cancers (Basel). 2021 Feb 2;13(3):581. doi: 10.3390/cancers13030581.
Prognosis for acute myeloid leukemia (AML) patients is poor, particularly in mutated AML, secondary, relapsed, and refractory AML, and in patients unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds targeting the stem cell oncoprotein BMI1 and activating the tumor suppressor protein p53 may represent a promising novel treatment option for poor risk AML patients.
The BMI1 inhibitor PTC596, MCL1 inhibitor S63845, and MEK inhibitor trametinib, as well as the p53 activator APR-246 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including and wild type, mutant and wild type, as well as mutant and wild type AML cell lines and a variety of patient derived AML cells.
AML cell lines were variably susceptible to PTC596 and to combination treatments with PTC596 and MCL1 inhibitor S63845, MEK inhibitor trametinib, or activator APR-246, independent of mutational status. Susceptibility of patient samples for PTC596 in combination with S63845 or trametinib was significant for the majority of adverse risk primary and secondary AML with minimal efficacy in favorable risk AML, and correlated significantly with CD34 positivity of the samples. and gene expression, and MCL1 and MEK1 protein levels were identified as biomarkers for response to PTC596 combination treatments.
The combination of PTC596 and S63845 may be an effective treatment in CD34+ adverse risk AML with elevated gene expression and MCL1 protein levels, while PTC596 and trametinib may be more effective in CD34+ adverse risk AML with elevated gene expression and MEK protein levels.
急性髓系白血病（AML）患者的预后较差，尤其是在突变型AML、继发性、复发性和难治性AML患者中，以及在不适合强化治疗的患者中，因此凸显了对新型治疗方法的未满足需求。联合使用靶向干细胞癌蛋白BMI1并激活肿瘤抑制蛋白p53的化合物可能是高危AML患者一种有前景的新型治疗选择。
评估BMI1抑制剂PTC596、MCL1抑制剂S63845和MEK抑制剂曲美替尼，以及p53激活剂APR - 246作为单一药物及其联合使用诱导白血病细胞凋亡和细胞死亡的能力。AML细胞代表所有主要形态学和分子亚型，包括野生型、突变型野生型、突变型野生型AML细胞系以及多种患者来源的AML细胞。
AML细胞系对PTC596以及PTC596与MCL1抑制剂S63845、MEK抑制剂曲美替尼或激活剂APR - 246联合治疗的敏感性各不相同，与突变状态无关。对于大多数高危原发性和继发性AML患者样本，PTC596联合S63845或曲美替尼具有显著疗效，而在低危AML中疗效甚微，且与样本的CD34阳性显著相关。基因表达、基因表达以及MCL1和MEK1蛋白水平被确定为对PTC596联合治疗反应的生物标志物。
PTC596与S63845联合使用可能是治疗基因表达和MCL1蛋白水平升高的CD34 +高危AML的有效方法，而PTC596与曲美替尼联合使用可能对基因表达和MEK蛋白水平升高的CD34 +高危AML更有效。
