pha-680632 and Multiple-Myeloma

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 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

Topics: Animals; Apoptosis; Aurora Kinase A; Aurora Kinase B; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; NF-kappa B; NF-kappaB-Inducing Kinase; Piperazines; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-abl; Pyrazoles; Pyrroles; STAT3 Transcription Factor; TNF Receptor-Associated Factor 2; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Constitutive activation of the canonical and noncanonical nuclear factor-κB (NF-κB) pathways is frequent in multiple myeloma (MM) and can compromise sensitivity to TRAIL. In this study, we demonstrate that Aurora kinases physically and functionally interact with the key regulators of canonical and noncanonical NF-κB pathways IκB kinase β (IKKβ) and IKKα to activate NF-κB in MM, and the pharmacological blockade of Aurora kinase activity induces TRAIL sensitization in MM because it abrogates TRAIL-induced activation of NF-κB. We specifically found that TRAIL induces prosurvival signaling by increasing the phosphorylation state of both Aurora and IKK kinases and their physical interactions, and the blockade of Aurora kinase activity by pan-Aurora kinase inhibitors (pan-AKIs) disrupts TRAIL-induced survival signaling by effectively reducing Aurora-IKK kinase interactions and NF-κB activation. Pan-AKIs consistently blocked TRAIL induction of the antiapoptotic NF-κB target genes A1/Bfl-1 and/or Mcl-1, both important targets for TRAIL sensitization in MM cells. In summary, these results identify a novel interaction between Aurora and IKK kinases and show that these pathways can cooperate to promote TRAIL resistance. Finally, combining pan-AKIs with TRAIL in vivo showed dramatic efficacy in a multidrug-resistant human myeloma xenograft model. These findings suggest that combining Aurora kinase inhibitors with TRAIL may have therapeutic benefit in MM.

Topics: Aged; Aged, 80 and over; Animals; Apoptosis; Aurora Kinase A; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Humans; I-kappa B Kinase; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Multiple Myeloma; Piperazines; Protein Kinase Inhibitors; Pyrazoles; Pyrroles; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Xenograft Model Antitumor Assays