Page 165 - 2019_10 resto del Mondo_web

Plasma Cell Disorders
Histone deacetylase inhibition in combination with MEK or BCL-2 inhibition in multiple myeloma
Ferrata Storti Foundation
Vijay G. Ramakrishnan,1* Kevin C. Miller,2* Elaine P. Macon,1 Teresa K. Kimlinger,1 Jessica Haug,1 Sanjay Kumar,1 Wilson I. Gonsalves,1 S. Vincent Rajkumar1 and Shaji K. Kumar1
1Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN and 2Mayo Clinic School of Medicine, Rochester, MN, USA
*VGR and KCM contributed equally to this work.
ABSTRACT
Despite recent advances in the treatment of multiple myeloma, patients with this disease still inevitably relapse and become refrac- tory 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 inhi- bition 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 specif- ically 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 deacety- lases 1 and 2 was sufficient to synergize with either MEK or BCL-2 inhibi- tion. Furthermore, these drug combinations effectively killed plasma cells from myeloma patients ex vivo. Given the preponderance of RAS/RAF muta- tions, 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.
Introduction
Multiple myeloma (MM) is a cancer of differentiated plasma cells.1 It evolves from a premalignant condition called monoclonal gammopathy of undetermined significance, which affects 5.3% of adults over the age of 70.2 More than 30,000 people are projected to be diagnosed with MM in the USA in 2018.3 Despite improvements in survival, MM remains incurable.1,4 In addition, it is a clinically het- erogeneous disease, with several major cytogenetic abnormalities that affect prog- nosis.5,6 Nevertheless, most patients receive uniform up-front treatment.1,6 Clearly, there is an unmet need for therapies that target particular drivers of the disease.
The RAS/RAF/MEK/ERK pathway is abnormally activated in MM through sev- eral mechanisms including oncogenic mutations and cytokines in the bone marrow microenvironment.7,8 Activating mutations in K-RAS, N-RAS and B-RAF have been reported in 50% of MM patients at diagnosis.7,9 Such mutations are present in <10% of patients with monoclonal gammopathy of undetermined significance,
Haematologica 2019 Volume 104(10):2061-2074
Parts of this manuscript were presented in abstract form at the American Association for Cancer Research (AACR) Annual Meeting on April 17, 2018 in Chicago, IL, USA.
Correspondence:
VIJAY G. RAMAKRISHNAN
ramakrishnan.vijay@mayo.edu
Received: November 16, 2018. Accepted: March 5, 2019. Pre-published: March 7, 2019.
doi:10.3324/haematol.2018.211110
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/10/2061
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(10)
2061
ARTICLE