Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia

Piovan, Erich; Yu, Jiyang; Tosello, Valeria; Herranz, Daniel; Ambesi-Impiombato, Alberto; Silva, Ana Carolina da; Sánchez-Martín, Marta; Pérez-García, Arianne; Rigo, Isaura; Castillo, Maurício; Indraccolo, Stefano; Cross, Justin R.; Stanchina, Elisa de; Paietta, Elisabeth; Racevskis, Janis; Rowe, Jacob M.; Tallman, Martin S.; Basso, Giuseppe; Meijerink, Jules P.P.; Cordon‐Cardo, Carlos; Califano, Andrea; Ferrando, Adolfo A.

doi:10.1016/j.ccr.2013.10.022

Cited by 236 publications

(247 citation statements)

References 34 publications

Supporting

Mentioning

228

Contrasting

Unclassified

Order By: Relevance

“…Additionally, the suppression of the PI3-kinase/Akt1 growth pathway by gene targeting or by the PI3-kinase inhibition has been shown to decrease tumor mass size (37). Interestingly, Piovan et al identify Akt1 as a negative regulator of GR␣ by phosphorylating serine 134, which resulted in GC resistance in T cell acute lymphoblastic leukemia (39). They also show that suppression of PTEN inhibits GR␣ expression and activity, enhances Akt phosphorylation, resulting in GCresistance.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

Stechschulte

Wuescher

Marino

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The glucocorticoid receptor ␤ (GR␤) is a positive regulator of growth. Results: GR␤ suppression of PTEN resulted in enhanced phosphorylation of Akt and growth. Conclusion: GR␤ enhances insulin-induced proliferation by suppressing PTEN and activating Akt1. Significance: GR␤ suppression of PTEN indicates that it has an important role in growth factor signaling and potentially cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

Stechschulte

Wuescher

Marino

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The corresponding human PC interactome was produced by ARACNe analysis of a set of gene expression profiles from~200 patient-derived PC samples, representing the full spectrum of disease progression. Comparison of the human and murine interactomes, using a novel algorithm, revealed that 70% of the regulatory programs in PC are highly conserved between these 2 species, including those of 2 synergistic master regulators (MRs) of progression to aggressive disease (forkhead box protein M1 and centromere protein F), inferred by the Master Regulator Inference algorithm (MARINa) [7,[12][13][14][15], and experimentally validated both in mouse and in human tissue. However, the analysis also showed that 30% of the programs are not conserved, including those representing a few PC-related genes that would thus be unlikely to produce patient-relevant results if studied or targeted in a murine context.…”

Section: Developing Human To Mouse To Human Approachesmentioning

confidence: 99%

“…This is accomplished by measuring the enrichment of over-and underexpressed genes in positively regulated and repressed targets in the regulon of every possible regulator protein represented in the interactome, thus providing an accurate and extremely robust predictor of the differential activity of a regulator. This has allowed the discovery of key functional drivers of tumorigenesis and drug sensitivity, including single regulators [13,15,[41][42][43], synergistic regulator pairs [4,12,14], and additive mechanisms that could not have been elucidated using traditional methods. Indeed, virtually none of the regulators that were experimentally validated were significantly differentially expressed at the RNA level and yet they were confirmed as individual or synergistic phenotypic drivers following identification by regulatory network analysis, thus elucidating novel mechanisms of disease initiation/ progression [4,12,13,[41][42][43][44][45][46], chemosensitivity [15,28], and normal physiologic regulation [14].…”

Section: Creating the Assembly Manual Of The Alzheimer's Cellmentioning

confidence: 99%

A Systems Approach to Drug Discovery in Alzheimer's Disease

et al. 2015

Self Cite

View full text Add to dashboard Cite

In the articles included in this volume, one feels a strong frustration among the writers with the slow course of therapeutics development for Alzheimer's disease and with the clinical failure of targeted therapeutic agents despite substantial progress in our understanding of the biology and biochemistry of the disease. Keywords Master regulator . Interactome . Human neuronsTo date, approaches to Alzheimer disease (AD) therapeutics have followed 2 main avenues. The first addresses neurotransmitter deficits in the early phases of the disease. This approach has led to the handful of AD drugs currently on the market that provide short-term symptomatic improvement but do not alter the course of the disease. The second approach has been directed at decreasing the burden of beta-amyloid (Aβ) in the brain by active or passive immunization or by inhibiting activity of β-or γ-secretases. To date, none of the approaches in this second class has been successful, although trials on β-or γ-secretase (BACE) inhibitors are ongoing.The lack of overt success has been even more frustrating because, in transgenic (Aβ-overproducing) mouse models of AD, Aβ-lowering approaches, as well as treatments with small molecules and biologics, have been successful in blocking memory loss, restoring memory function, reversing dendritic spine alterations, and reversing inhibition of longterm potentiation [1][2][3]. Indeed, as animal models only partially recapitulate the human AD phenotype and because human brain tissue is available only postmortem, translation of preclinical findings to the clinics has been fraught with difficulties.For instance, the characteristic intraneuronal neurofibrillary tangles and extensive neuronal loss observed in human AD are absent in mouse models of the disease. This dichotomy suggests that mouse models replicate only presymptomatic AD stages, while clinical manifestations appear only after neuronal loss becomes irreversible. This hypothesis is directly addressed by ongoing trials, where individuals with genetic mutations that predispose to early AD onset are being treated with Aβ-targeted therapies to assess whether presymptomatic treatment may block an otherwise certain disease progression. Beyond Aβ-targeted therapies, novel approaches are being developed based on inhibition of tau phosphorylation and aggregation, and on blockade of synaptic loss, leveraging "candidate" target approaches derived from human and animal data. Unfortunately, it has so far been impossible to discern whether "candidate genes" represent causal determinants of the disease process or are the downstream result of them.In this review, we will discuss the potential of adapting integrative systems biology approaches that have already proven extremely valuable in understanding multiple cancer related phenotypes to human neurodegenerative diseases.

show abstract

“…88 In these cases, too, NOTCH-inhibiting therapies may be more effective when combined with AKT inhibitors. Furthermore, enhanced AKT activity may limit leukemia sensitivity to steroid treatment, 89,90 one of the cornerstone drugs in the treatment of human T-ALL. AKT was shown to directly phosphorylate (S134) and inactivate the steroid receptor NR3C1.…”

Section: Rd Mendes Et Almentioning

confidence: 99%

“…AKT was shown to directly phosphorylate (S134) and inactivate the steroid receptor NR3C1. 89 Combined steroid treatment with the dual PI3K-mTOR inhibitor BEZ235 91 or the MK2206 AKT inhibitor 89 sensitized AKT-activated leukemic cells to steroid treatment.…”

Section: Rd Mendes Et Almentioning

confidence: 99%

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

et al. 2016

View full text Add to dashboard Cite

T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of developing T cells in the thymus. T-ALL is characterized by chromosomal rearrangements. These rearrangements can lead to the aberrant activation of oncogenic transcription factors by placing their genes under the control of promoters and/or enhancers of Tcell receptor genes, the BCL11B gene, or other genes; occasionally, these rearrangements can give rise to oncogenic fusion proteins. The activated oncogenic transcription factors include TAL1 and LMO2 (and related family members), TLX1, TLX3, NKX2-1, HOXA, and MEF2C; in addition, certain oncogenic fusion proteins can directly activate the HOXA or MEF2C genes.1,2 Oncogenic proteins facilitate the developmental arrest of pre-leukemic immature T cells. We previously proposed that these chromosomal rearrangements should be classified as type A aberrations, as they are generally considered to be the driving oncogenic event associated with unique expression profiles.2 Based upon their gene expression signatures, T-ALL can be classified into the following four major subtypes: ETP-ALL, TLX, proliferative, and TALLMO. [3][4][5] Maturation arrest induces a pre-leukemic condition in which additional mutations can give rise to T-ALL.1,2 These secondary mutations are not necessarily clonal events and are often selected during disease progression or post-treatment T he tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT. Based on these models and on observations in primary diagnostic samples from patients with T-cell acute lymphoblastic leukemia, we speculate that PTEN-deficient cells employ an intrinsic homeostatic mechanism in which PI3K-AKT signaling is dampened over time. As a result of this reduced PI3K-AKT signaling, the level of AKT activation may be insufficient to compensate for NOTCH1 inhibition, resulting in responsiveness to gamma-secretase inhibitors. On the other hand, de novo acquired PTEN-inactivating events in NOTCH1-dependent leukemia could result in temporary, strong activation of PI3K-AKT signaling, increased glycoly sis and glutaminolysis, and consequently gamma-secretase inhibitor resistance. Due to the central role of PTEN-AKT signaling and in the resistance to NOTCH1 inhibition, AKT inhibitors may be a promising addition to current treatment protocols for T-cell acute lymphoblastic leukemia.

show abstract

Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia

Cited by 236 publications

References 34 publications

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

A Systems Approach to Drug Discovery in Alzheimer's Disease

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

Contact Info

Product

Resources

About