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

Reikvam, Håkon; Nepstad, Ina; Tamburini, Jérôme

doi:10.1517/13543784.2013.841137

Cited by 9 publications

(3 citation statements)

References 15 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is commonly accepted that a disparity in the regulation of protein kinases may be one of the primary causes of genetic-based human diseases, and a major part of new drug development over the last decades has been dedicated to the development of protein kinase inhibitors [115]. The PI3K-Akt-mTOR pathway has emerged as a possible therapeutic target in human malignancies, and several pharmacological inhibitors have been developed, including isoform-selective or pan-class I PI3K inhibitors, Akt inhibitors, rapamycin, and rapalogs as well as dual PI3K-mTOR inhibitors [116].…”

Section: Inhibition Of the Pi3k-akt-mtor Pathway In Amlmentioning

confidence: 99%

“…The numbers of mutant signaling proteins identified in AML are high [9], although are more likely to reflect activation of a limited number of downstream effector pathways [115]. Targeting of these unifying pathways hence may represent a more broadly applicable therapeutic strategy, emphasizing the potential rational for combination therapy in AML [139].…”

Section: Conclusion and Further Perspectivementioning

confidence: 99%

See 1 more Smart Citation

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

Nepstad

Hatfield

Grønningsæter

et al. 2020

IJMS

Self Cite

205

150

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by uncontrolled proliferation of hematopoietic stem cells in the bone marrow. Malignant cell growth is characterized by disruption of normal intracellular signaling, caused by mutations or aberrant external signaling. The phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway (PI3K-Akt-mTOR pathway) is among one of the intracellular pathways aberrantly upregulated in cancers including AML. Activation of this pathway seems important in leukemogenesis, and given the central role of this pathway in metabolism, the bioenergetics of AML cells may depend on downstream signaling within this pathway. Furthermore, observations suggest that constitutive activation of the PI3K-Akt-mTOR pathway differs between patients, and that increased activity within this pathway is an adverse prognostic parameter in AML. Pharmacological targeting of the PI3K-Akt-mTOR pathway with specific inhibitors results in suppression of leukemic cell growth. However, AML patients seem to differ regarding their susceptibility to various small-molecule inhibitors, reflecting biological heterogeneity in the intracellular signaling status. These findings should be further investigated in both preclinical and clinical settings, along with the potential use of this pathway as a prognostic biomarker, both in patients receiving intensive curative AML treatment and in elderly/unfit receiving AML-stabilizing treatment.

show abstract

Section: Inhibition Of the Pi3k-akt-mtor Pathway In Amlmentioning

confidence: 99%

Section: Conclusion and Further Perspectivementioning

confidence: 99%

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

Nepstad

Hatfield

Grønningsæter

et al. 2020

IJMS

Self Cite

205

150

View full text Add to dashboard Cite

show abstract

“…Development of mutations in the kinase domain, has been described as an acquired form of drug resistance, responsible for this phenomenon 89 . This has been well-described with sorafenib with subsequent development of the D835 mutation 77 .…”

Section: Novel Flt3 Mutations and Resistance To Flt3 Inhibitorsmentioning

confidence: 99%

Investigational FMS-like tyrosine kinase 3 inhibitors in treatment of acute myeloid leukemia

Pemmaraju

Kantarjian

Andreeff

et al. 2014

Expert Opinion on Investigational Drugs

View full text Add to dashboard Cite

Introduction Outcomes for the majority of patients with Acute Myeloid Leukemia (AML) remain poor. Over the past decade, significant progress has been made in the understanding of the cytogenetic and molecular determinants of AML pathogenesis. One such advance is the identification of recurring mutations in the FMS-like tyrosine kinase 3 gene(FLT3). Currently, this marker, which appears in approximately one third of all AML patients, signifies a poorer prognosis, but also identifies an important target for therapy. FLT3 kinase inhibitors have now undergone clinical evaluation in phase I, II and III clinical trials, as both single agents and in combination with chemotherapeutics. Unfortunately, to date, none of the FLT3 inhibitors have gained FDA approval for the treatment of patients with AML. Yet, there are several promising FLT3 inhibitors are being evaluated in all phases of drug development. Areas covered This review aims to highlight the agents furthest along in their development. It also focuses on those FLT3 inhibitors that are being evaluated in combination with other anti-leukemia agents. Expert opinion The authors believe that the field of research for FLT3 inhibitors remains promising, despite the historically poor prognosis of this subgroup of patients with AML. The most promising areas of research will likely be the elucidation of the mechanisms of resistance to FLT3 inhibitors, and development of potent FLT3 inhibitors alone, or in cominbation with hypomethylating agents, cytotoxic chemotherapy, or with other targeted agents.

show abstract

The cytokine-mediated crosstalk between primary human acute myeloid cells and mesenchymal stem cells alters the local cytokine network and the global gene expression profile of the mesenchymal cells

et al. 2015

View full text Add to dashboard Cite

Interactions between acute myeloid leukemia (AML) blasts and neighboring stromal cells are important for disease development and chemosensitivity. However, the molecular mechanisms involved in the cytokine-mediated crosstalk between mesenchymal stem cells (MSCs) and AML cells are largely unknown. Leukemic cells derived from 18 unselected AML patients were cultured with bone marrow MSCs derived from healthy donors; the populations then being separated by a semipermeable membrane. Coculture had only minor effects on MSC proliferation. The unique cytokine network in cocultures was determined by high constitutive MSC release of certain cytokines (especially IL-6 and vascular endothelial growth factor) and constitutive release of a wide range of soluble mediators by primary AML cells. However, the AML cell release varied considerably between patients, and these differences between patients were also reflected in the coculture levels even though supra-additive effects were seen for many mediators. These effects on the local cytokine network were dependent on a functional crosstalk between the two cell subsets. The crosstalk altered the global gene expression profile of the MSCs, especially expression of genes encoding proteins involved in downstream signaling from Toll like receptors, NFκB signaling and CCL/CXCL chemokine release. Thus, primary AML cells alter the functional phenotype of normal MSCs.

show abstract

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

Cited by 9 publications

References 15 publications

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

Investigational FMS-like tyrosine kinase 3 inhibitors in treatment of acute myeloid leukemia

The cytokine-mediated crosstalk between primary human acute myeloid cells and mesenchymal stem cells alters the local cytokine network and the global gene expression profile of the mesenchymal cells

Contact Info

Product

Resources

About