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

PloS one (2014-11-12)
Esperanza Martín-Sánchez, Lina Odqvist, Socorro M Rodríguez-Pinilla, Margarita Sánchez-Beato, Giovanna Roncador, Beatriz Domínguez-González, Carmen Blanco-Aparicio, Ana M García Collazo, Esther González Cantalapiedra, Joaquín Pastor Fernández, Soraya Curiel del Olmo, Helena Pisonero, Rebeca Madureira, Carmen Almaraz, Manuela Mollejo, F Javier Alves, Javier Menárguez, Fernando González-Palacios, José Luis Rodríguez-Peralto, Pablo L Ortiz-Romero, Francisco X Real, Juan F García, James R Bischoff, Miguel A Piris
ABSTRAKT

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.

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