Antileukaemic effect of PI3K‐mTOR inhibitors in acute myeloid leukaemia‐gene expression profiles reveal CDC25B expression as determinate of pharmacological effect

Abstract

SummaryAcute myeloid leukaemia (AML) is a heterogeneous malignancy. Intracellular signalling through the phosphatidylinositol 3‐kinase (PI3K)‐Akt‐mammalian target of rapamycin (mTOR) pathway is important for regulation of cellular growth and metabolism, and inhibitors of this pathway is considered for AML treatment. Primary human AML cells, derived from 96 consecutive adult patients, were examined. The effects of two mTOR inhibitors (rapamycin, temsirolimus) and two PI3K inhibitors (GDC‐0941, 3‐methyladenine) were studied, and we investigated cytokine‐dependent proliferation, regulation of apoptosis and global gene expression profiles. Only a subset of patients demonstrated strong antiproliferative effects of PI3K‐mTOR inhibitors. Unsupervised hierarchical clustering analysis identified two main clusters of patients; one subset showing weak or absent antiproliferative effects (59%) and another group showing a strong growth inhibition for all drugs and concentrations examined (41%). Global gene expression analyses showed that patients with AML cell resistance against PI3K‐mTOR inhibitors showed increased mRNA expression of the CDC25B gene that encodes the cell cycle regulator Cell Division Cycle 25B. The antileukaemic effect of PI3K‐Akt‐mTOR inhibition varies between patients, and resistance to these inhibitors is associated with the expression of the cell cycle regulator CDC25B, which is known to crosstalk with the PI3K‐Akt‐mTOR pathway and mediate rapamycin resistance in experimental models.

Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

“…Our recent observation that resistance against PI3K/mTOR inhibitors in primary human AML cells was associated with increased mRNA expression of CDC25B also supports the hypothesis that CDC25 inhibition will increase the anticancer effects of PI3K/mTOR inhibition, but at least for AML this combined strategy showed an increased efficiency only for certain patients [89].…”

“…High expression is associated with resistance against the antiproliferative effect of PI3K-Akt-mTOR inhibitors [89], but the molecular mechanisms behind this effect are not known. Inhibition of this isoform seems to reduce AML cell line proliferation through effects on NF-YB and p300 [88]; whereas in other cells growth inhibition is seen only with combined Cyclin D1 and CDC25B inhibition [84].…”

“…The most important studies are presented in detail in Table 1 [49,[83][84][85][86][87][88][89][90][91], but it should be emphasized that several of these studies are relatively small, describe observations mainly in AML cell lines or used methodological strategies that would not be regarded as optimal today. Thus, knowledge about CDC25 in human AML is in our opinion incomplete, but despite this CDC25 should be regarded as a possible therapeutic target in human AML.…”

“…Inhibition of the PI3K-Akt-mTOR pathway is now considered for the treatment of human AML [89]. However, a recent study described that the mTOR inhibitor rapamycin affected the phosphorylation status of 250 phosphorylation sites in 161 cellular proteins, including several kinases and phosphatases [61].…”

Predicting effects of kinase inhibitor in therapy for myeloid malignancies – the challenges in capturing disease heterogeneity

“…This is supported by evidence that drug can induce different effects among some patients and, on the other hand, induce only opposite unwanted effect in other patients [2,3]. Fan et al describe a novel nanoscalar proteomic assay to identify the susceptibility of myelodysplastic syndrome (MDS) patients to rigosertib, a dual non-ATP inhibitor of polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase pathways (PI3K) [1].…”