Alexander Peter M, Kucera Gregory L, Pladna Kristin M, Pardee Timothy S
Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, NC.
Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, NC; Cancer Biology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC.
Transl Oncol. 2020 Jul;13(7):100780. doi: 10.1016/j.tranon.2020.100780. Epub 2020 May 16.
Acute myeloid leukemia (AML) is an aggressive malignancy with poor outcomes. Nucleoside analogs are subject to resistance mechanisms including downregulation of equilibrative nucleoside transporter (ENT1) and deoxycytidine kinase (dCK). KPC34 is a novel phospholipid mimetic that when cleaved by phospholipase C (PLC) liberates gemcitabine monophosphate and a diacylglycerol mimetic that inhibits the classical isoforms of protein kinase C (PKC). KPC34 acts independently of ENT1 and dCK. KPC34 was active against all AML cell lines tested with ICs in the nanomolar range. Enforced expression of PLC increased response to KPC34 in vivo. In an orthotopic, xenograft model, KPC34 treatment resulted in a significant increase in survival compared to control animals and those treated with high-dose cytarabine. In a PDX model with activated PKC, there was a significant survival benefit with KPC34, and at progression, there was attenuation of PKC activation in the resistant cells. In contrast, KPC34 was ineffective against a syngeneic, orthotopic AML model without activated PKC. However, when cells from that model were forced to express PKC, there were significantly increased sensitivity in vitro and survival benefit in vivo. These data suggest that KPC34 is active against AML and that the presence of activated PKC can be a predictive biomarker.
急性髓系白血病（AML）是一种侵袭性恶性肿瘤，预后较差。核苷类似物易产生耐药机制，包括平衡核苷转运体（ENT1）和脱氧胞苷激酶（dCK）的下调。KPC34是一种新型磷脂模拟物，被磷脂酶C（PLC）切割后可释放吉西他滨单磷酸和一种抑制蛋白激酶C（PKC）经典亚型的二酰基甘油模拟物。KPC34的作用独立于ENT1和dCK。KPC34对所有测试的AML细胞系均有活性，IC50在纳摩尔范围内。在体内，强制表达PLC可增加对KPC34的反应。在原位异种移植模型中，与对照动物和接受大剂量阿糖胞苷治疗的动物相比，KPC34治疗可显著提高生存率。在具有激活型PKC的人源肿瘤异种移植（PDX）模型中，KPC34具有显著的生存获益，并且在疾病进展时，耐药细胞中的PKC激活减弱。相比之下，KPC34对没有激活型PKC的同基因原位AML模型无效。然而，当该模型中的细胞被强制表达PKC时，其在体外的敏感性显著增加，在体内具有生存获益。这些数据表明，KPC34对AML有活性，并且激活型PKC的存在可能是一种预测性生物标志物。
