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ABT-737 is highly effective against molecular subgroups of multiple myeloma
Linda Bodet1, Patricia Gomez-Bougie, Cyrille Touzeau
1Inserm, Unité Mixte de Recherche_S892, Institut de Recherche Thérapeutique de l'Université de Nantes, Nantes, France.
Abstract:
Multiple myeloma is a plasma cell malignancy that is heterogeneous with respect to its causative molecular abnormalities and the treatment response of patients. The Bcl-2 protein family is critical for myeloma cell survival. ABT-737 is a cell-permeant compound that binds to Bcl-2 and Bcl-x(L) but not to Mcl-1. Using a myeloma cell line collection (n = 25) representative of different molecular translocations, we showed that ABT-737 effectively kills a subset of cell lines (n = 6), with a median lethal dose ranging from 7 ± 0.4 nM to 150 ± 7.5 nM. Of interest, all sensitive cell lines harbored a t(11;14). We demonstrated that ABT-737-sensitive and ABT-737-resistant cell lines could be differentiated by the BCL2/MCL1 expression ratio. A screen of a public expression database of myeloma patients indicates that the BCL2/MCL1 ratio of t(11;14) and hyperdiploid patients was significantly higher than in all other groups (P < .001). ABT-737 first induced the disruption of Bcl-2/Bax, Bcl-2/Bik, or Bcl-2/Puma complexes, followed by the disruption of Bcl-2 heterodimers with Bak and Bim. Altogether, the identification of a subset of cell lines and primary cells effectively killed by ABT-737 alone supported the evaluation of ABT-263, an orally active counterpart to ABT-737, for the treatment of t(11;14) and hyperdiploid groups of myeloma harboring a Bcl-2(high)/Mcl-1(low) profile.
Insights
ABT-737 effectively kills a subset of multiple myeloma cell lines, particularly those with t(11;14) translocation. Sensitivity is linked to a high BCL2/MCL1 expression ratio, suggesting targeted therapy potential.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Multiple myeloma is a heterogeneous plasma cell malignancy.
- The Bcl-2 protein family plays a crucial role in myeloma cell survival.
- ABT-737 targets Bcl-2 and Bcl-x(L), inhibiting myeloma cell survival.
Purpose of the Study:
- To investigate the efficacy of ABT-737 in killing multiple myeloma cell lines.
- To identify molecular predictors of ABT-737 sensitivity in myeloma.
- To explore the potential of ABT-737 and its oral counterpart ABT-263 for specific myeloma subtypes.
Main Methods:
- Utilized a collection of 25 myeloma cell lines representing diverse molecular abnormalities.
- Assessed ABT-737 efficacy using median lethal dose (nM) measurements.
- Analyzed BCL2/MCL1 expression ratios and protein complex disruptions.
- Screened a public myeloma patient expression database.
Main Results:
- ABT-737 demonstrated potent killing of a subset (n=6) of myeloma cell lines (median lethal dose 7–150 nM).
- Sensitivity to ABT-737 was strongly associated with the t(11;14) translocation.
- A high BCL2/MCL1 expression ratio differentiated sensitive from resistant cell lines.
- The BCL2/MCL1 ratio was significantly higher in t(11;14) and hyperdiploid myeloma patients.
Conclusions:
- ABT-737 effectively targets a specific subset of multiple myeloma cells, particularly those with t(11;14).
- The BCL2/MCL1 expression ratio serves as a predictive biomarker for ABT-737 sensitivity.
- These findings support the clinical evaluation of ABT-263 for t(11;14) and hyperdiploid myeloma with a Bcl-2(high)/Mcl-1(low) profile.
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