PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases

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.

Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

“…The likely existence of compensatory mechanisms among the three isoforms of Pim kinase, Pim-1, Pim-2 and Pim-3, supports the utility of developing pan-Pim kinase inhibitors [36]. Four Pim kinase inhibitors have entered clinical trials to date.…”

“…Doxorubicin-induced DNA damage was significantly increased in lymphoma cell lines exposed to a Pim kinase inhibitor, in association with significant downregulation of the DNA DSB response proteins H2AX, ATM and Chk2 [57]. Similarly, inhibition of Pim kinase in T-cell lymphoma cells downregulated genes involved in DNA repair, including XRCC2 (HR) , XRCC5 (encoding Ku80, in the NHEJ pathway), and ERCC8 (nucleotide excision repair) [36]. Pim kinase inhibition was also found to potentiate paclitaxel-induced apoptosis through decreased repair via the NHEJ pathway, with inhibition of ATM, DNA-PKcs and Ku activity and/or expression [58].…”

Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110α inhibition

“…For instance, PIM2 phosphorylates and inhibits the pro-apoptotic protein Bcl-2-associated death promoter (BAD) and also targets the eukaryotic translation initiation factor 4B (eIF4B) [4]. Accordingly, pharmacological PIM inhibition induces apoptosis and/or suppresses the proliferation of peripheral T cell lymphoma cells [5], chronic lymphocytic leukemia cells [6], and myeloid leukemia cells [7–9]. In addition to hematopoietic malignancies, PIM kinases are also overexpressed in a variety of solid tumors, including prostate and pancreatic cancer, gastric, colorectal and liver carcinomas, squamous cell carcinoma and bladder cancer [2].…”

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

“…PIM1 decreases sensitivity to ALK TKIs in ALK-positive ALCL. Given that a strong synergistic effect was previously shown on simultaneous inhibition of ALK and PIM kinases in ALK-positive ALCL cell lines 46 , PIM1 was overexpressed and sensitivity to ALK inhibitors monitored in ALK-positive ALCL cell lines. Karpas 299 and SU-DHL-1 cells were transduced to express components of the CRISPR SAM complex whose activity was confirmed (Supplementary Fig.…”