Institut Cochin, CNRS UMR8104, INSERM U1016, Université de Paris, Paris, France.
FILOthèque, Hôpital La Pitié-Salpêtrière, Paris, France.
Eur J Haematol. 2020 Nov;105(5):588-596. doi: 10.1111/ejh.13492. Epub 2020 Aug 4.
Venetoclax combined with hypomethylating agents is a new therapeutic strategy frequently used for treating AML patients who are not eligible for conventional chemotherapy. However, high response rates are heterogeneous due to different mechanisms mediating resistance to venetoclax such as up-regulation of MCL-1 expression. We thus tested the anti-leukemic activity of S63845, a specific MCL-1 inhibitor.
Apoptosis induces by S63845 with or without venetoclax was evaluated in primary AML samples and in AML cell lines co-cultured or not with bone marrow (BM) mesenchymal stromal cells. Sensitivity of leukemic cells to S63845 was correlated to the expression level of BCL-2, MCL-1, and BCL-XL determined by Western Blot and mass spectrometry-based proteomics.
We observed that even if MCL-1 expression is weak compared to BCL-2, S63845 induces apoptosis of AML cells and strongly synergizes with venetoclax. Furthermore, AML cells resistant to venetoclax are highly sensitive to S63845. Interestingly, the synergistic effect of S63845 toward venetoclax-mediated apoptosis of AML cells is still observed in a context of interaction with the BM microenvironment that intrinsically mediates resistance to BCL2 inhibition.
These results are therefore of great relevance for clinicians as they provide the rational for combining BCL-2 and MCL-1 inhibition in AML.
维奈托克联合低甲基化剂是一种新的治疗策略，常用于治疗不适合常规化疗的 AML 患者。然而，由于介导对维奈托克耐药的机制不同，高缓解率存在异质性，如 MCL-1 表达上调。因此，我们测试了 S63845（一种特异性 MCL-1 抑制剂）的抗白血病活性。
在原代 AML 样本和与骨髓（BM）间充质基质细胞共培养或不共培养的 AML 细胞系中，评估 S63845 联合或不联合维奈托克诱导的细胞凋亡。通过 Western blot 和基于质谱的蛋白质组学确定 BCL-2、MCL-1 和 BCL-XL 的表达水平，来评估白血病细胞对 S63845 的敏感性。
我们观察到，即使与 BCL-2 相比，MCL-1 的表达较弱，S63845 也能诱导 AML 细胞凋亡，并与维奈托克强烈协同作用。此外，对维奈托克耐药的 AML 细胞对 S63845 高度敏感。有趣的是，在与内在介导 BCL2 抑制耐药的 BM 微环境相互作用的背景下，S63845 对维奈托克介导的 AML 细胞凋亡的协同作用仍然存在。
这些结果对临床医生具有重要意义，因为它们为在 AML 中联合抑制 BCL-2 和 MCL-1 提供了合理依据。
