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Haematologica. 2019 Apr 4. pii: haematol.2018.208280. doi: 10.3324/haematol.2018.208280. [Epub ahead of print]

Functional interplay between NIK and c-Abl kinases limits response to Aurora inhibitors in multiple myeloma.

Author information

1
University of Parma; Isituto Zooprofilattico Sperimentale Lombardia Emilia Romagna.
2
University of Parma.
3
Isituto Zooprofilattico Sperimentale Lombardia Emilia Romagna.
4
University of Bari Aldo Moro.
5
University of Parma; Centre for Molecular and Translational Oncology.
6
University of Parma; Centre for Molecular and Translational Oncology p.lunghi@libero.it.

Abstract

Considering that Aurora kinase inhibitors are currently under clinical investigation in hematological cancers, the identification of molecular events that limit the response to such agents is essential for enhancing 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 downregulation of its negative regulator TRAF2; accumulated NIK converts c-Abl tyrosine 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 PIMs survival kinases consistently enhances Myeloma cells'responsiveness to Aurora inhibitors. Importantly, concurrent inhibition of NIK or c-Abl disrupts Aurora inhibitors-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 therapies for MM. 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 PIMs survival kinases as potential pharmacological targets for improving the efficacy of Aurora inhibitors in Myeloma.

KEYWORDS:

Aurora kinase inhibitors; NF-κB inducing kinase (NIK); Pim kinases; Tyrosine kinase inhibitors; c-Abl

PMID:
30948493
DOI:
10.3324/haematol.2018.208280
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