title: Antileukaemic effect of PI3K-mTOR inhibitors in acute myeloid leukaemia-gene expression profiles reveal CDC25B expression as determinate of pharmacological effect.
abstract: Acute 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.
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway; Division of Haematology, Department of Medicine, Haukeland University, Bergen, Norway.
authors.forename: Håkon
authors.initials: H
authors.lastname: Reikvam
authors.forename: Jerome
authors.initials: J
authors.lastname: Tamburini
authors.forename: Silje
authors.initials: S
authors.lastname: Skrede
authors.forename: Rita
authors.initials: R
authors.lastname: Holdhus
authors.forename: Laury
authors.initials: L
authors.lastname: Poulain
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ersvaer
authors.forename: Kimberley J
authors.initials: KJ
authors.lastname: Hatfield
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D016207:Cytokines / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059467:Transcriptome; D016896:Treatment Outcome; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D000970:Antineoplastic Agents; D016207:Cytokines; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases
keywords: CDC25B; acute myeloid leukaemia; mammalian target of rapamycin; pharmacological intervention; phosphatidylinositol 3-kinase