Loss of PIM2 enhances the anti-proliferative effect of the pan-PIM kinase inhibitor AZD1208 in non-Hodgkin lymphomas

Sarah Kreuz, K. B. Holmes, R. M. Tooze, P. F. Lefevre*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Background: A promising therapeutic approach for aggressive B-cell Non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma (BL) is to target kinases involved in signal transduction and gene regulation. PIM1/2 serine/threonine kinases are highly expressed in activated B-cell-like DLBCL (ABC-DLBCL) with poor prognosis. In addition, both PIM kinases have a reported synergistic effect with c-MYC in mediating tumour development in several cancers, c-MYC gene being translocated to one of the immunoglobulin loci in nearly all BLs. Methods: For these reasons, we tested the efficiency of several PIM kinase inhibitors (AZD1208, SMI4a, PIM1/2 inhibitor VI and Quercetagetin) in preventing proliferation of aggressive NHL-derived cell lines and compared their efficiency with PIM1 and/or PIM2 knockdown. Results: We observed that most of the anti-proliferative potential of these inhibitors in NHL was due to an off-target effect. Interestingly, we present evidence of a kinase-independent function of PIM2 in regulating cell cycle. Moreover, combining AZD1208 treatment and PIM2 knockdown additively repressed cell proliferation. Conclusion: Taken together, this study suggests that at least a part of PIM1/2 oncogenic potential could be independent of their kinase activity, justifying the limited anti-tumorigenic outcome of PIM-kinase inhibitors in NHL.

Original languageEnglish (US)
Article number205
JournalMolecular Cancer
Volume14
Issue number1
DOIs
StatePublished - Dec 8 2015

Keywords

  • BL
  • C-MYC
  • DLBCL
  • Lymphoma
  • PIM kinase

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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