Page 151 - 2019_12-Haematologica-web

Plasma Cell Disorders
Functional interplay between NF-κB-inducing kinase and c-Abl kinases limits response to Aurora inhibitors in multiple myeloma
Ferrata Storti Foundation
Haematologica 2019 Volume 104(12):2465-2481
Laura Mazzera,1,2 Manuela Abeltino,1 Guerino Lombardi,2
Anna Maria Cantoni,3 Roberto Ria,4 Micaela Ricca,2 Ilaria Saltarella,4 Valeria Naponelli,1 Federica Maria Angela Rizzi,1,5 Roberto Perris,5,6 Attilio Corradi,3 Angelo Vacca,4 Antonio Bonati1,5 and Paolo Lunghi5,6
1Department of Medicine and Surgery, University of Parma, Parma; 2Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna “Bruno Ubertini,” Brescia; 3Department of Veterinary Science, University of Parma, Parma; 4Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari "Aldo Moro" Medical School, Bari; 5Center for Molecular and Translational Oncology, University of Parma, Parma and 6Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
ABSTRACT
Considering that Aurora kinase inhibitors are currently under clinical investigation in hematologic cancers, the identification of molecular events that limit the response to such agents is essential for enhanc- ing clinical outcomes. Here, we discover a NF-κB-inducing kinase (NIK)-c- Abl-STAT3 signaling-centered feedback loop that restrains the efficacy of Aurora inhibitors in multiple myeloma. Mechanistically, we demonstrate that Aurora inhibition promotes NIK protein stabilization via downregula- tion of its negative regulator TRAF2. Accumulated NIK converts c-Abl tyro- sine kinase from a nuclear proapoptotic into a cytoplasmic antiapoptotic effector by inducing its phosphorylation at Thr735, Tyr245 and Tyr412 residues, and, by entering into a trimeric complex formation with c-Abl and STAT3, increases both the transcriptional activity of STAT3 and expression of the antiapoptotic STAT3 target genes PIM1 and PIM2. This consequently promotes cell survival and limits the response to Aurora inhibition. The functional disruption of any of the components of the trimer NIK-c-Abl- STAT3 or the PIM survival kinases consistently enhances the responsive- ness of myeloma cells to Aurora inhibitors. Importantly, concurrent inhibi- tion of NIK or c-Abl disrupts Aurora inhibitor-induced feedback activation of STAT3 and sensitizes myeloma cells to Aurora inhibitors, implicating a combined inhibition of Aurora and NIK or c-Abl kinases as potential thera- pies for multiple myeloma. Accordingly, pharmacological inhibition of c- Abl together with Aurora resulted in substantial cell death and tumor regression in vivo. The findings reveal an important functional interaction between NIK, Abl and Aurora kinases, and identify the NIK, c-Abl and PIM survival kinases as potential pharmacological targets for improving the effi- cacy of Aurora inhibitors in myeloma.
Introduction
Despite encouraging advances in therapy, multiple myeloma (MM) remains an incurable disease due to complex genomic alterations, lower sensitivity to chemotherapy of MM cells in the bone marrow microenvironment, and the emer- gence of drug resistance.1
Recent genetic evidence has established a pathogenetic role for NF-κB signaling in MM.2-4 In particular, at various frequencies, MM cells harbor gain-of-function mutations as well as loss-of-function mutations in genes encoding components of the classical and the alternative NF-κB pathways.2-4 Among these, mutations in the genes encoding NF-κB-inducing kinase (NIK) or its negative regulators TRAF2,
Correspondence:
PAOLO LUNGHI
p.lunghi@libero.it
Received: Ocrtober 17, 2018. Accepted: April 3, 2019. Pre-published: April 4, 2019.
doi:10.3324/haematol.2018.208280
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/12/2465
©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(12)
2465
ARTICLE