Grundy Martin, Balakrishnan Sahana, Fox Matthew, Seedhouse Claire H, Russell Nigel H
Clinical Haematology, Nottingham University Hospitals, Nottingham, United Kingdom.
Department of Haematology, Division of Cancer and Stem Cells, University of Nottingham, Nottingham, United Kingdom.
Oncotarget. 2018 Dec 28;9(102):37777-37789. doi: 10.18632/oncotarget.26540.
Acute myeloid leukaemia (AML) cells often up-regulate pro-survival members of the BCL-2 protein family, such as BCL-2 and MCL-1, to avoid apoptosis. Venetoclax (ABT-199) targets BCL-2 and has shown promising efficacy in AML but over-expression of MCL-1 can cause resistance. A co-operative approach, targeting both BCL-2 and MCL-1 may therefore prove beneficial. This study investigated the potential synergistic relationship between Venetoclax and the MCL-1 inhibitor S63845 in AML cells. We treated MV4-11 cells and primary AML samples for 4 hours with Venetoclax, S63845 or the combination. We used a short-term flow cytometric technique to assess synergy using cytochrome C release as a read out of response. The combination of Venetoclax and S63845 produced a synergistic apoptotic response in MV4-11 cells and primary samples, including the leukaemia re-populating leukaemic stem cell (LSC) population, in 92% of the samples. Known molecular biomarkers of response to BCL-2 and MCL-1 targeting agents were corroborated, and augmented, with the short-term functional assay. The assay also predicted potential biomarkers of response to the combination of BCL-2 and MCL-1 targeting agents. Primary samples with an IDH2_140 mutation were more sensitive to Venetoclax as a single agent whereas samples with a FLT3-ITD mutation were more resistant. This resistance could be reversed when combined with S63845. All FLT3-ITD and NPM1 mutated samples were sensitive to the combination of drugs. We report that co-operatively targeting BCL-2 and MCL-1 may be beneficial in AML and a short-term assay can identify patients who might best respond to this combination.
急性髓系白血病（AML）细胞通常会上调BCL-2蛋白家族的促生存成员，如BCL-2和MCL-1，以避免细胞凋亡。维奈托克（ABT-199）靶向BCL-2，在AML中已显示出有前景的疗效，但MCL-1的过表达可导致耐药。因此，一种同时靶向BCL-2和MCL-1的联合方法可能被证明是有益的。本研究调查了维奈托克与MCL-1抑制剂S63845在AML细胞中的潜在协同关系。我们用维奈托克、S63845或两者联合处理MV4-11细胞和原发性AML样本4小时。我们使用一种短期流式细胞术技术，以细胞色素C释放作为反应的读出指标来评估协同作用。维奈托克和S63845的联合在92%的样本中，对MV4-11细胞和原发性样本，包括白血病再增殖白血病干细胞（LSC）群体，产生了协同凋亡反应。对靶向BCL-2和MCL-1药物反应的已知分子生物标志物通过短期功能试验得到了证实和补充。该试验还预测了对靶向BCL-2和MCL-1药物联合反应的潜在生物标志物。具有IDH2_140突变的原发性样本对单药维奈托克更敏感，而具有FLT3-ITD突变的样本更耐药。当与S63845联合时，这种耐药性可以被逆转。所有FLT3-ITD和NPM1突变的样本对联合用药敏感。我们报告，联合靶向BCL-2和MCL-1在AML中可能是有益的，并且短期试验可以识别出可能对这种联合治疗反应最佳的患者。
