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PLoS One. 2014 Nov 11;9(11):e112148. doi: 10.1371/journal.pone.0112148. eCollection 2014.

PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases.

Author information

1
Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Cancer Genomics Group, Marqués de Valdecilla Research Institute (IDIVAL) & Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
2
Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
3
Pathology Department, Fundación Jiménez Díaz, Madrid, Spain.
4
Onco-hematology Area, Instituto de Investigación Sanitaria Hospital Universitario Puerta de Hierro - Majadahonda, Madrid, Spain.
5
Monoclonal Antibodies Core Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
6
Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
7
Cancer Genomics Group, Marqués de Valdecilla Research Institute (IDIVAL) & Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
8
Pathology Department, Hospital Virgen de la Salud, Toledo, Spain.
9
Pathology Department, Hospital La Paz, Madrid, Spain.
10
Pathology Department, Hospital Gregorio Marañón, Madrid, Spain.
11
Pathology Department, Hospital Ramón y Cajal, Madrid, Spain.
12
Pathology Department, 12 de Octubre University Hospital, Medical School Universidad Complutense, Instituto i+12, Madrid, Spain.
13
Dermatology Department, 12 de Octubre University Hospital, Medical School Universidad Complutense, Instituto i+12, Madrid, Spain.
14
Translational Research Laboratory, M. D. Anderson Cancer Center Madrid, Madrid, Spain.

Abstract

Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL). The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs) and pharmacologically (mainly with the pan-PIM inhibitor (PIMi) ETP-39010) in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL) cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.

PMID:
25386922
PMCID:
PMC4227704
DOI:
10.1371/journal.pone.0112148
[Indexed for MEDLINE]
Free PMC Article

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