PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases.
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.
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.
Esperanza
E
Martín-Sánchez
Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Lina
L
Odqvist
Pathology Department, Fundación Jiménez Díaz, Madrid, Spain.
Socorro M
SM
Rodríguez-Pinilla
Onco-hematology Area, Instituto de Investigación Sanitaria Hospital Universitario Puerta de Hierro - Majadahonda, Madrid, Spain.
Margarita
M
Sánchez-Beato
Monoclonal Antibodies Core Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Giovanna
G
Roncador
Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Beatriz
B
Domínguez-González
Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Carmen
C
Blanco-Aparicio
Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Ana M
AM
García Collazo
Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Esther González
EG
Cantalapiedra
Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Joaquín Pastor
JP
Fernández
Cancer Genomics Group, Marqués de Valdecilla Research Institute (IDIVAL) & Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Soraya
S
Curiel del Olmo
Cancer Genomics Group, Marqués de Valdecilla Research Institute (IDIVAL) & Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Helena
H
Pisonero
Cancer Genomics Group, Marqués de Valdecilla Research Institute (IDIVAL) & Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Rebeca
R
Madureira
Cancer Genomics Group, Marqués de Valdecilla Research Institute (IDIVAL) & Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Carmen
C
Almaraz
Pathology Department, Hospital Virgen de la Salud, Toledo, Spain.
Manuela
M
Mollejo
Pathology Department, Hospital La Paz, Madrid, Spain.
F Javier
FJ
Alves
Pathology Department, Hospital Gregorio Marañón, Madrid, Spain.
Javier
J
Menárguez
Pathology Department, Hospital Ramón y Cajal, Madrid, Spain.
Fernando
F
González-Palacios
Pathology Department, 12 de Octubre University Hospital, Medical School Universidad Complutense, Instituto i+12, Madrid, Spain.
José Luis
JL
Rodríguez-Peralto
Dermatology Department, 12 de Octubre University Hospital, Medical School Universidad Complutense, Instituto i+12, Madrid, Spain.
Pablo L
PL
Ortiz-Romero
Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Francisco X
FX
Real
Translational Research Laboratory, M. D. Anderson Cancer Center Madrid, Madrid, Spain.
Juan F
JF
García
Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
James R
JR
Bischoff
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.
Miguel A
MA
Piris
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D006801:Humans; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D034741:RNA, Small Interfering
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim; D002945:Cisplatin