TY - JOUR
T1 - Histone deacetylase inhibition in combination with MEK or BCL-2 inhibition in multiple myeloma
AU - Ramakrishnan, Vijay G.
AU - Miller, Kevin C.
AU - Macon, Elaine P.
AU - Kimlinger, Teresa K.
AU - Haug, Jessica
AU - Kumar, Sanjay
AU - Gonsalves, Wilson I.
AU - Vincent Rajkumar, S.
AU - Kumar, Shaji K.
N1 - Funding Information:
We thank Dr. Scott Kaufmann, M.D., Ph.D. for helpful discussions and commentary during the writing of this manuscript. We also thank the patients and their families for the gracious donation of their bone marrow aspirates to our laboratory. This work was funded by the Predolin Foundation, Mayo Clinic Hematology Small Grants Program, International Myeloma Foundation, CTSA grant number TL1TR002380 from the National Center for Advancing Translational Sciences (NCATS), Mayo Clinic Multiple Myeloma SPORE, Wendy Will Case Cancer Fund, Mayo Clinic Development Funds from the Myeloma, Amyloidosis and Dysproteinemia Disease Oriented Group (MADDOG), and the Mayo Clinic Office of Translation to Practice. Additionally, we would like to thank the American Association for Cancer Research for a Scholar-in-Training Award, and the American Society of Hematology for an HONORS award.
Publisher Copyright:
© 2019 Ferrata Storti Foundation
PY - 2019
Y1 - 2019
N2 - 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 anti-apoptotic 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 promise as biomarker-driven therapies.
AB - 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 anti-apoptotic 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 promise as biomarker-driven therapies.
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U2 - 10.3324/haematol.2018.211110
DO - 10.3324/haematol.2018.211110
M3 - Article
C2 - 30846494
AN - SCOPUS:85072847724
SN - 0390-6078
VL - 104
SP - 2061
EP - 2074
JO - Haematologica
JF - Haematologica
IS - 10
ER -