Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells.
Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells.
复制标题
DOI：
10.18632/oncotarget.26540
复制
发表时间：
2018-12-28
期刊：
影响因子：
--
通讯作者：
Russell, Nigel H
中科院分区：
文献类型：
--
作者：
Grundy, Martin;Balakrishnan, Sahana;Russell, Nigel H
急性髓性白血病（AML）细胞通常上调BCL-2蛋白家族的促存活成员，如BCL-2和MCL-1，以避免细胞凋亡。维奈托克（ABT-199）靶向BCL-2，并在AML中显示出有希望的疗效，但MCL-1的过度表达可能导致耐药性。因此，针对BCL-2和MCL-1的合作方法可能是有益的。本研究探讨了维奈托克和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或其组合处理MV 4 -11细胞和原代AML样品4小时。我们使用了短期流式细胞术技术，以评估协同作用，细胞色素C的释放作为读出的响应。维奈托克和S63845联合给药在MV 4 -11细胞和原代样本中产生了协同凋亡反应，包括92%的样本中的白血病再增殖白血病干细胞（LSC）群体。对BCL-2和MCL-1靶向剂的应答的已知分子生物标志物通过短期功能测定得到证实和增强。该测定还预测了对BCL-2和MCL-1靶向剂的组合的响应的潜在生物标志物。具有IDH2_140突变的原代样本对维奈托克单药更敏感，而具有FLT 3-ITD突变的样本更耐药。当与S63845组合时，该抗性可以逆转。所有FLT 3-ITD和NPM 1突变样品对药物组合敏感。我们报告说，合作靶向BCL-2和MCL-1可能是有益的AML和短期的体外试验可以确定谁可能最好地响应这种组合的患者。
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 in vitro assay can identify patients who might best respond to this combination.