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Mol Cancer. 2015 Dec 8;14:205. doi: 10.1186/s12943-015-0477-z.

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

Author information

1
Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, The Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK. sarah_kreuz@gmx.net.
2
Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, The Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK. medkho@leeds.ac.uk.
3
Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, The Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK. R.Tooze@leeds.ac.uk.
4
Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, The Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK. p.lefevre@leeds.ac.uk.

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.

PMID:
26643319
PMCID:
PMC4672512
DOI:
10.1186/s12943-015-0477-z
[Indexed for MEDLINE]
Free PMC Article

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