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Published on: October 5, 2012
Histone deacetylase inhibition in combination with MEK or BCL-2 inhibition in multiple myeloma
Vijay G Ramakrishnan1, Kevin C Miller2, Elaine P Macon3
1Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN ramakrishnan.vijay@mayo.edu.
Abstract:
Despite recent advances in the treatment of multiple myeloma, patients with this disease still inevitably relapse and become refractory to existing therapies. Mutations in K-RAS, N-RAS and B-RAF are common in multiple myeloma, affecting 50% of patients at diagnosis and >70% at relapse. However, targeting mutated RAS/RAF via MEK inhibition is merely cytostatic in myeloma and largely ineffective in the clinic. We examined mechanisms mediating this resistance and identified histone deacetylase inhibitors as potent synergistic partners. Combining the MEK inhibitor AZD6244 (selumetinib) with the pan-histone deacetylase inhibitor LBH589 (panobinostat) induced synergistic apoptosis in RAS/RAF mutated multiple myeloma cell lines. Interestingly, this synergy was dependent on the pro-apoptotic protein BIM. We determined that while single-agent MEK inhibition increased BIM levels, the protein remained sequestered by antiapoptotic BCL-2 family members. LBH589 dissociated BIM from MCL-1 and BCL-XL, which allowed it to bind BAX/BAK and thereby initiate apoptosis. The AZD6244/LBH589 combination was specifically active in cell lines with more BIM:MCL-1 complexes at baseline; resistant cell lines had more BIM:BCL-2 complexes. Those resistant cell lines were synergistically killed by combining the BH3 mimetic ABT-199 (venetoclax) with LBH589. Using more specific histone deacetylase inhibitors, i.e. MS275 (entinostat) and FK228 (romidepsin), and genetic methods, we determined that concomitant inhibition of histone deacetylases 1 and 2 was sufficient to synergize with either MEK or BCL-2 inhibition. Furthermore, these drug combinations effectively killed plasma cells from myeloma patients ex vivo Given the preponderance of RAS/RAF mutations, and the fact that ABT-199 has demonstrated clinical efficacy in relapsed/refractory multiple myeloma, these drug combinations hold prom ise as biomarker-driven therapies.
Insights
Targeting mutated RAS/RAF in multiple myeloma with MEK inhibitors is ineffective alone. Combining MEK inhibitors with histone deacetylase inhibitors, like panobinostat, synergistically kills myeloma cells by releasing the pro-apoptotic protein BIM.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multiple myeloma patients often relapse and become refractory to treatments.
- Mutations in RAS/RAF genes are prevalent in multiple myeloma, increasing with relapse.
- Current MEK inhibition therapy for RAS/RAF-mutated myeloma shows limited clinical efficacy, primarily acting as a cytostatic agent.
Purpose of the Study:
- To investigate mechanisms of resistance to MEK inhibition in multiple myeloma.
- To identify synergistic drug combinations to overcome MEK inhibitor resistance.
- To explore the role of histone deacetylase inhibitors and BIM in overcoming resistance.
Main Methods:
- Utilized MEK inhibitor AZD6244 (selumetinib) and pan-histone deacetylase inhibitor LBH589 (panobinostat) in multiple myeloma cell lines.
- Assessed synergistic apoptosis induction and the role of the pro-apoptotic protein BIM.
- Investigated BIM's interaction with antiapoptotic BCL-2 family members (MCL-1, BCL-XL, BCL-2) and its release via histone deacetylase inhibition.
- Tested combinations with BH3 mimetic ABT-199 (venetoclax) for resistant cell lines.
- Employed specific histone deacetylase inhibitors (entinostat, romidepsin) and genetic methods.
- Evaluated drug combination efficacy on primary patient cells ex vivo.
Main Results:
- Combining AZD6244 and LBH589 induced synergistic apoptosis in RAS/RAF-mutated myeloma cells.
- Synergy was dependent on BIM release from MCL-1 and BCL-XL, enabling BAX/BAK activation.
- Cell lines with higher baseline BIM:MCL-1 complexes responded better to AZD6244/LBH589.
- Cell lines with higher BIM:BCL-2 complexes were sensitive to LBH589/ABT-199 combination.
- Concomitant inhibition of histone deacetylases 1 and 2 synergized with MEK or BCL-2 inhibition.
- Drug combinations effectively killed primary myeloma cells ex vivo.
Conclusions:
- Histone deacetylase inhibitors are potent synergistic partners for MEK inhibitors in multiple myeloma.
- The BIM:MCL-1 complex is a potential biomarker for response to MEK inhibitor/histone deacetylase inhibitor combinations.
- The BIM:BCL-2 complex may predict response to BCL-2 inhibitor/histone deacetylase inhibitor combinations.
- Targeting histone deacetylases 1 and 2 is crucial for overcoming resistance.
- Biomarker-driven combinations of MEK inhibitors, BCL-2 inhibitors, and histone deacetylase inhibitors show promise for treating relapsed/refractory multiple myeloma.
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