Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients

Abstract

The phosphoinositide 3-kinase (PI3K/Akt) pathway is activated in acute myelogenous leukemia (AML) and is promising for targeted inhibition. Ninety-two patients with primary AML were analyzed for PI3K/Akt constitutive activation. Fifty percent of the patients presented with constitutive PI3K activation (PI3K ؉ ). No difference was observed between PI3K ؉ and PI3K ؊ groups concerning age, sex, white blood cell count, lactate dehydrogenase (LDH) level, bone marrow blast cells, French-American-British (FAB) classification, cytogenetics, RAS or nucleophosmin (NPM) mutations. Slightly more FLT3-ITD was detected in the PI3K ؊ group (P ‫؍‬ .048). The complete remission rate was similar between the 2 groups. With a median follow-up of 26 months, we observed for PI3K ؉ and PI3K ؊ patients, respectively, 56% and 33% overall survival (P ‫؍‬ .001) and 72% and 41% relapse-free IntroductionSeveral recent articles have highlighted that the class IA phosphoinositide 3-kinase/serine-threonine kinase (PI3K)/Akt pathway is activated in acute myelogenous leukemia (AML), both in blast cells and in the immature CD34 ϩ , CD38 Low , and CD123 ϩ population. 1-4 Most PI3K activity in AML is caused by the p110␦ isoform of PI3K, the activity of which can be specifically inhibited by IC87114. 5,6 The mechanisms leading to PI3K activation are unclear and no activating mutation in the PI3KCD gene coding this isoform has been identified. 7 Two studies have suggested that the prognosis of AML patients with an upregulated PI3K/Akt pathway is worst, suggesting that this pathway could constitute a therapeutic target. 2,8 To ascertain this hypothesis, we prospectively studied constitutive PI3K/Akt/ FOXO3A activation in 92 de novo AML patients. Patients, materials, and methods PatientsNinety-two patients with de novo AML treated in the AML-2001 trial from the Groupe Ouest-Est des Leucémies et Autres Maladies du Sang (GOELAMS) were included, after approval by the GOELAMS Institutional Review Board and receipt of signed informed consent in accordance with the Declaration of Helsinki. The patients received cytosine-arabinoside (200 mg/m 2 , days 1-7) and daunorubicin (60 mg/m 2 , days 1-3) or idarubicin (8 mg/m 2 , days 1-5), and a second course (daunorubicin 35 mg/m 2 , days 17-18 or idarubicin 8 mg/m 2 , days 17-18, and cytosine-arabinoside 1 g/m 2 every 12 hours days 17-20) if bone marrow blasts were more than 5% at day 15. All patients in complete remission received low-dose consolidation with daunorubicin (60 mg/m 2 , days 1-2) or idarubicin (12 mg/m 2 , days 1-2), and cytosine-arabinoside (100 mg/m 2 , days 1-7). Patients with HLAidentical siblings underwent allogenic stem cell transplant (up front until 50 years old; after a consolidation and with a reduced intensity conditioning after 51 years old). Other patients received one consolidation (idarubicin 12 mg/m 2 or daunorubicin 60 mg/m 2 , days 1-2 and cytosine-arabinoside 3g/m 2 every 12 hours days 1-4), followed by autologous stem cell transplantation or high-dose chemotherapy in favorable-ri...

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…2 The genes encoding the PI3K catalytic and regulatory chains are members of multi-gene families. Historically, the p110a isoform has been the best-characterized catalytic subunit; however, it has been recently shown that the p110d isoform may play a larger role in leukemogenesis [3][4][5] and tumor surveillance than expected previously. The activation of the PI3Kd isoform does not appear to be due to genetic mutations.…”

Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy

“…Cells harboring these mutations may be refractory to Akt inhibitors which target the kinase domain but may be more sensitive to inhibitors which target the PH domain (Carpten et al, 2007). The role of overexpression of the different Akt isoforms in cancer prognosis is controversial (Kornblau et al, 2006, Tamburini et al, 2007. Some studies have suggested that elevated Akt expression is associated with a poor prognosis in breast (Kirkegaard et al, 2005) and hematopoietic (Kornblau et al, 2006) cancers.…”

“…Some studies have suggested that elevated Akt expression is associated with a poor prognosis in breast (Kirkegaard et al, 2005) and hematopoietic (Kornblau et al, 2006) cancers. Controversially it has been observed recently that constitutive PI3K/Akt activation is a favorable prognostic factor in AML patients (Tamburini et al, 2007) as Akt activation may keep a high percentage of the cells in S phase which renders them sensitive to chemotherapeutic drugs. These and other studies document the complexity of enhanced Akt expression which may make certain cells more sensitive or resistant to certain anti-cancer therapies.…”

The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML

“…[3][4][5] Studies have shown that the PI3K/Akt/mTOR pathway is constitutively activated in 50-70% of acute myeloid leukemia (AML) cases, suggesting that this pathway could constitute a therapeutic target. [6][7][8][9][10][11] p53 is the most frequently inactivated protein in human cancer, and more than 50% of all solid tumors carry p53 mutations in the TP53 gene that abrogate its DNA binding and transactivation activity. 12 Although TP53 mutations rarely occur in AML, it has been suggested that inactivation of wild-type p53 frequently occurs through binding to its principal cellular regulator murine double minute 2 homologue (Mdm2).…”