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Pairing MCL‐1 inhibition with venetoclax improves therapeutic efficiency of BH3‐mimetics in AML
Author(s) -
Hormi Myriam,
Birsen Rudy,
Belhadj Maya,
Huynh Tony,
Cantero Aguilar Lilia,
Grignano Eric,
Haddaoui Lamya,
Guillonneau Francois,
Mayeux Patrick,
Hunault Mathilde,
Tamburini Jérôme,
Kosmider Olivier,
Fontenay Michaela,
Bouscary Didier,
Chapuis Nicolas
Publication year - 2020
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.13492
Subject(s) - venetoclax , cancer research , apoptosis , context (archaeology) , chemistry , stromal cell , bone marrow , leukemia , medicine , immunology , biology , biochemistry , paleontology , chronic lymphocytic leukemia
Objectives 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. Methods 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. Results 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. Conclusion These results are therefore of great relevance for clinicians as they provide the rational for combining BCL‐2 and MCL‐1 inhibition in AML.