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L. Mazzera et al.
Figure 13. Schematic representation of our proposed molecular model for NIK/c-Abl/STAT3/PIM axis in multiple myeloma (MM) cells. (a) Under basal conditions, NF-κB-inducing kinase (NIK) is degraded through the TRAF2/TRAF3/cIAP1/2 complex and, because of constitutive DNA damage and activation of the DNA damage response network, c-Abl is primarily localized in the nucleus. (b) Upon treatment with Aurora kinase inhibitors TRAF2 is degraded and NIK accumulates. (c) Accumulated NIK induces cytoplasmic relocalization and activation of c-Abl by promoting its phosphorylation at Thr735, Tyr 245 and Tyr 412; (d) NIK and c-Abl co- operate to form a complex with and phosphorylate STAT3 at Ser727 and Tyr705, thus increasing its transcriptional activity and leading to the upregulation of the anti-apoptotic STAT3-target genes PIM1 and PIM2. (e) PIM induction reduces drug response; depletion or inactivation of any of the tri-complex components as well as PIM kinases potentiates the anti-myeloma activity of Aurora inhibitors.
demonstrated that MK-0457 is able to inhibit the autophosphorylation of T315I mutant BCR-ABL at con- centrations (IC50 values ranging from 5 to 10 μM)49,51,52 which are significantly higher than those clinically achiev- able (plasma/serum concentrations 1-3 μM)48,50,53 and 12.5- 100-fold greater than those required to inhibit Aurora kinases and exert its anti-tumor activities.49,51 Particular attention was, therefore, given here to assay the effects of MK-0457 at submolar concentrations (0.1-0.4 μM) in all of our in vitro experiments.
Interestingly, MK-0457, in its cytostatic and/or cytotoxic potential, did not discriminate between parental and wild- type or mutants BCR-ABL-transformed Ba/F3 cells.49,52 However, hematologic responses were also observed in patients treated with MK-0457 at clinical doses that had not been reported to affect BCR-ABL kinase activity.50 This would suggest that the activity of the drug is mainly exerted through inhibition of Aurora kinases rather than by interference with BCR-ABL function.
Finally, a role for c-Abl in the activation of STAT3 has been reported,13,38 as well as a connection between c-Abl and
Mcl-1 in chronic myelogenous and lymphocytic leukemias.13,54 Indeed, we have previously showed that pan- AKIs were capable of up-regulating Mcl-1 in MM cells.25
Thus, cytoplasmic relocalization and activation of c-Abl secondary to NIK cytoplasmic accumulation, together with the formation of NIK/c-Abl/STAT3 trimeric com- plexes, emerge as novel survival mechanisms that signifi- cantly impair the antitumor efficacy of pan-AKI and iden- tify potential translational approaches for targeting these mechanisms by using pan-AKI in combination with NIK, c-Abl, STAT3 and/or PIM inhibitors (Figure 13).
Funding
This work was supported by grants from “Chiara Tassoni” Onlus Association, Parma, Italy (LM), Associazione Italiana per la Ricerca sul Cancro (IG, Rif 10670, Italian Association for Cancer Research, Milan, Italy; AB), and Fondazione Cassa di Risparmio di Parma (Cariparma, Parma, Italy; AB). This work was supported by the Italian Ministry of Health (GR-2016- 02363646 to LM) and by Regione Emilia Romagna L. 20/2002 (GPG/2018/918 to PL).
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