Session: 652. Myeloma: Pathophysiology and Pre-Clinical Studies, excluding Therapy: Targeting MCL1 and Other Molecular Vulnerabilities in Multiple Myeloma
Hematology Disease Topics & Pathways:
apoptosis, Biological Processes
Among this cohort of MM patients, 47 samples were further analyzed for the presence of recurrent translocations (t(11;14), t(6;14), t(4;14) and t(14;16)) allowing the analysis of dependencies in the different subgroups; these recurrent translocations lead to the overexpression of CCND1, CCND3, MMSET and MAF oncogenes, respectively. We found that BCL2 dependency was significantly higher in CCND1 subgroup (83%) compared to all other subgroups (20%, p=0.008). We also confirmed the BCL2/BCLXL mRNA ratio as a valuable biomarker to define BCL2 dependence (p=0.0001). At diagnosis, MCL1 dependency was absent in patients not harboring the common recurrent translocations while at relapse 6 out 9 patients not harboring the recurrent translocations were MCL1 dependent, indicating an increase of MCL1 dependency at relapse in this subgroup (p=0.03).
Mechanistically, we demonstrated that BAK is crucial for cell death induced by MCL1 mimetic A1210477, according to the protection of cell death observed by BAK knock-down and the complete disruption of MCL1/BAK complexes upon A1210477 treatment, observed in MM cell lines and also in a patient sample. Interestingly, this complex was also dissociated in A1210477 resistant cells but free BAK was simultaneously recaptured by BCLXL, supporting the role of BCLXL in A1210477 resistance. Thus, BCLXL may act as a sink to bind freed pro-apoptotic proteins from MCL1 and limits MM cell death triggered by the specific targeting of MCL1.
In conclusion, our study highlights the potential clinical use of BH3 mimetics in MM treatment guided by the practical ex-vivo testing of myeloma cell dependencies using the BH3 toolkit. This strategy could be used to identify the respective and tailored use of venetoclax, MCL1 BH3 mimetics or their combination in myeloma treatment.
Disclosures: Moreau: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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