Page 270 - Haematologica March 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):784-795
Plasma Cell DIsorders
Kinome expression profiling to target new therapeutic avenues in multiple myeloma
Hugues de Boussac,1 Angélique Bruyer,1 Michel Jourdan,1 Anke Maes,2
Nicolas Robert,3 Claire Gourzones,1 Laure Vincent,4 Anja Seckinger,5,6 Guillaume Cartron,4,7,8 Dirk Hose,5,6 Elke De Bruyne,2 Alboukadel Kassambara,1 Philippe Pasero1 and Jérôme Moreaux1,3,8
1IGH, CNRS, Université de Montpellier, Montpellier, France; 2Department of Hematology
and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels,
3
Belgium; CHU Montpellier, Laboratory for Monitoring Innovative Therapies, Department
of Biological Hematology, Montpellier, France; 4CHU Montpellier, Department of Clinical Hematology, Montpellier, France; 5Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany; 6Nationales Centrum für Tumorerkrankungen, Heidelberg , Germany; 7Université de Montpellier, UMR CNRS 5235, Montpellier, France and 8 Université de Montpellier, UFR de Médecine, Montpellier, France
ABSTRACT
Multiple myeloma (MM) account for approximately 10% of hematological malignancies and is the second most common hematological disorder. Kinases inhibitors are widely used and their efficiency for the treatment of cancers has been demonstrated. Here, in order to identify kinases of potential therapeutic interest for the treatment of MM, we investigated the prognostic impact of the kinome expression profile in large cohorts of patients. We identified 36 kinome- related genes significantly linked with a prognostic value to MM, and built a kinome index based on their expression. The Kinome Index (KI) is linked to prognosis, proliferation, differentiation, and relapse in MM. We then tested inhibitors targeting seven of the identified protein kinas- es (PBK, SRPK1, CDC7-DBF4, MELK, CHK1, PLK4, MPS1/TTK) in human myeloma cell lines. All tested inhibitors significantly reduced the viability of myeloma cell lines, and we confirmed the potential clinical interest of three of them on primary myeloma cells from patients. In addition, we demonstrated their ability to potentialize the toxicity of conventional treatments, including Melphalan and Lenalidomide. This highlights their potential beneficial effect in myeloma therapy. Three kinases inhibitors (CHK1i, MELKi and PBKi) overcome resistance to Lenalidomide, while CHK1, PBK and DBF4 inhibitors re-sensitize Melphalan resistant cell line to this conventional therapeutic agent. Altogether, we demonstrate that kinase inhibitors could be of therapeu- tic interest especially in high-risk myeloma patients defined by the KI. CHEK1, MELK, PLK4, SRPK1, CDC7-DBF4, MPS1/TTK and PBK inhibitors could represent new treatment options either alone or in com- bination with Melphalan or IMiD for refractory/relapsing myeloma patients.
Introduction
MM is the second most common hematological disorder,1 and is characterized by the clonal accumulation of malignant plasma cells in the bone marrow.2 MM is a genetically and clinically heterogeneous disease and genome sequencing studies have recently revealed considerable heterogeneity and genomic instability, a com- plex mutational landscape and a branching pattern of clonal evolution.3,4
Novel agents have been developed in MM including the proteasome inhibitors bortezomib and carfilzomib, and the immunomodulatory drugs thalidomide, Lenalidomide and pomalidomide.5 However, patients invariably relapse after mul- tiple lines of treatment, with shortened intervals in between relapses, and finally
Correspondence:
JEROME MOREAUX, jerome.moreaux@igh.cnrs.fr
Received: October 5, 2018. Accepted: July 5, 2019. Pre-published: July 9, 2019.
doi:10.3324/haematol.2018.208306
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/784
©2020 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.
784
haematologica | 2020; 105(3)
ARTICLE