scholarly journals Article Commentary: Emerging Role of Tyrosine Kinases as Drugable Targets in Cancer

2015 ◽  
Vol 10s3 ◽  
pp. BMI.S22432 ◽  
Author(s):  
Il-Kang Na ◽  
Philipple Coutre
Keyword(s):  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Drug Target ◽  
Cell Function ◽  
Resistance Mechanisms ◽  
Fda Approval ◽  
Medical Oncologists ◽  
Tk Inhibitors ◽  
Inhibitor Treatment

Tyrosine kinases (TKs) play a significant role in cancerogenesis and cancer cell function. Initial developments in this field go back to the early 80s, but the success story really started with the selective BCR-ABL inhibitor, imatinib. Owing to the cancer-driving role of BCR-ABL in chronic myeloid leukemia (CML), excellent response rates lead to fast FDA approval in both the first and second treatments of CML patients. Since then, numerous TKs were identified. TK inhibitors have been developed accordingly, and technology to test for ideal drug–target interactions has profoundly improved. By now, medical oncologists and hematologists struggle to have a pool of potential TK inhibitors, where the most efficient one could be picked out to treat a specific cancer patient, which might also help overcome the occurring resistance mechanisms against TK inhibitors. Whether disease eradication can be achieved via single or sequential TK inhibitor treatment(s) needs to be tested in the present and in the future.

scholarly journals High HSPA8 expression predicts adverse outcomes of acute myeloid leukemia

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jun Li ◽  
Zheng Ge
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Cell Function ◽  
Adverse Outcomes ◽  
High Expression ◽  
Micro Rnas ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) remains one of the most common hematological malignancies, posing a serious challenge to human health. HSPA8 is a chaperone protein that facilitates proper protein folding. It contributes to various activities of cell function and also is associated with various types of cancers. To date, the role of HSPA8 in AML is still undetermined. Methods In this study, public datasets available from the TCGA (Cancer Genome Atlas) and GEO (Gene Expression Omnibus) were mined to discover the association between the expression of HSPA8 and clinical phenotypes of CN-AML. A series of bioinformatics analysis methods, including functional annotation and miRNA-mRNA regulation network analysis, were employed to investigate the role of HSPA8 in CN-AML. Results HSPA8 was highly expressed in the AML patients compared to the healthy controls. The high HSPA8 expression had lower overall survival (OS) rate than those with low HSPA8 expression. High expression of HSPA8 was also an independent prognostic factor for overall survival (OS) of CN-AML patients by multivariate analysis. The differential expressed genes (DEGs) associated with HSPA8 high expression were identified, and they were enriched PI3k-Akt signaling, cAMP signaling, calcium signaling pathway. HSPA8 high expression was also positively associated with micro-RNAs (hsa-mir-1269a, hsa-mir-508-3p, hsa-mir-203a), the micro-RNAs targeted genes (VSTM4, RHOB, HOBX7) and key known oncogenes (KLF5, RAN, and IDH1), and negatively associated with tumor suppressors (KLF12, PRKG1, TRPS1, NOTCH1, RORA). Conclusions Our research revealed HSPA8 as a novel potential prognostic factor to predict the survival of CN-AML patients. Our data also revealed the possible carcinogenic mechanism and the complicated microRNA-mRNA network associated with the HSPA8 high expression in AML.

E3 ligase–defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4197-4208 ◽  
Author(s):  
Srinivasa Rao Bandi ◽  
Christian Brandts ◽  
Marion Rensinghoff ◽  
Rebekka Grundler ◽  
Lara Tickenbrock ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Receptor Tyrosine Kinases ◽  
E3 Ligase ◽  
Myeloproliferative Disease ◽  
Primary Resistance ◽  
Murine Bone Marrow

Abstract Somatic mutations of Kit have been found in leukemias and gastrointestinal stromal tumors. The proto-oncogene c-Cbl negatively regulates Kit and Flt3 by its E3 ligase activity and acts as a scaffold. We recently identified the first c-Cbl mutation in human disease in an acute myeloid leukemia patient, called Cbl-R420Q. Here we analyzed the role of Cbl mutants on Kit-mediated transformation. Coexpression of Cbl-R420Q or Cbl-70Z with Kit induced cytokine-independent proliferation, survival, and clonogenic growth. Primary murine bone marrow retrovirally transduced with c-Cbl mutants and transplanted into mice led to a generalized mastocytosis, a myeloproliferative disease, and myeloid leukemia. Overexpression of these Cbl mutants inhibited stem cell factor (SCF)–induced ubiquitination and internalization of Kit. Both Cbl mutants enhanced the basal activation of Akt and prolonged the ligand-dependent activation. Importantly, transformation was observed also with kinase-dead forms of Kit and Flt3 in the presence of Cbl-70Z, but not in the absence of Kit or Flt3, suggesting a mechanism dependent on receptor tyrosine kinases, but independent of their kinase activity. Instead, transformation depends on the Src family kinase Fyn, as c-Cbl coimmunoprecipitated with Fyn and inhibition abolished transformation. These findings may explain primary resistance to tyrosine kinase inhibitors targeted at receptor tyrosine kinases.

scholarly journals Disruption of SIRPα signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts

2012 ◽  
Vol 209 (10) ◽  
pp. 1883-1899 ◽  
Author(s):  
Alexandre P.A. Theocharides ◽  
Liqing Jin ◽  
Po-Yan Cheng ◽  
Tatiana K. Prasolava ◽  
Andrei V. Malko ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Function ◽  
Leukemia Stem Cell ◽  
Tumor Surveillance ◽  
Human Acute Myeloid Leukemia ◽  
Differential Ability ◽  
Acute Myeloid

Although tumor surveillance by T and B lymphocytes is well studied, the role of innate immune cells, in particular macrophages, is less clear. Moreover, the existence of subclonal genetic and functional diversity in some human cancers such as leukemia underscores the importance of defining tumor surveillance mechanisms that effectively target the disease-sustaining cancer stem cells in addition to bulk cells. In this study, we report that leukemia stem cell function in xenotransplant models of acute myeloid leukemia (AML) depends on SIRPα-mediated inhibition of macrophages through engagement with its ligand CD47. We generated mice expressing SIRPα variants with differential ability to bind human CD47 and demonstrated that macrophage-mediated phagocytosis and clearance of AML stem cells depend on absent SIRPα signaling. We obtained independent confirmation of the genetic restriction observed in our mouse models by using SIRPα-Fc fusion protein to disrupt SIRPα–CD47 engagement. Treatment with SIRPα-Fc enhanced phagocytosis of AML cells by both mouse and human macrophages and impaired leukemic engraftment in mice. Importantly, SIRPα-Fc treatment did not significantly enhance phagocytosis of normal hematopoietic targets. These findings support the development of therapeutics that antagonize SIRPα signaling to enhance macrophage-mediated elimination of AML.

scholarly journals Lower RNA expression of ALDH1A1 distinguishes the favorable risk group in acute myeloid leukemia

2021 ◽  
Author(s):  
Garrett M. Dancik ◽  
Ioannis F. Voutsas ◽  
Spiros A. Vlahopoulos
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Rna Expression ◽  
Poor Overall Survival ◽  
Activity Of Enzymes ◽  
Acute Myeloid

The expression and activity of enzymes that belong to the aldehyde dehydrogenases is a characteristic of both normal and malignant stem cells. ALDH1A1 is an enzyme critical in cancer stem cells. In acute myeloid leukemia (AML), ALDH1A1 protects leukemia-initiating cells from a number of antineoplastic agents, which include inhibitors of protein tyrosine kinases. Furthermore, ALDH1A1 proves vital for the establishment of human AML xenografts in mice. We review here important studies characterizing the role of ALDH1A1 in AML and its potential as a therapeutic target. We also analyze datasets from leading studies, and show that decreased ALDH1A1 RNA expression consistently characterizes the AML patient risk group with a favorable prognosis, while there is a consistent association of high ALDH1A1 RNA expression with high risk and poor overall survival. Our review and analysis reinforces the notion to employ both novel as well as existing inhibitors of the ALDH1A1 protein against AML.

Bruton’s Tyrosine Kinase (BTK) Is Not Required for BCR-ABL-Mediated Transformation of Hematopoietic Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1015-1015 ◽  
Author(s):  
Mary MacPartlin ◽  
Lee A. Honigberg ◽  
Brian J. Druker ◽  
Michael W. Deininger
Keyword(s):  
Cell Proliferation ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Drug Target ◽  
Hematopoietic Cells ◽  
Kinase Domain ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Imatinib Resistant

Abstract Background: Bruton’s tyrosine kinase (BTK) is a member of the Tec family of protein tyrosine kinases. Mutations of BTK have been associated with a block in B cell development, and are causal to X-linked agammaglobulinemia (XLA) in humans. Bcr-Abl is a constitutively active tyrosine kinase that is essential for the transforming capacity of Bcr-Abl. Using phosphoproteomics we have shown that BTK is consistently tyrosine phosphorylated in Bcr-Abl expressing Ba/F3 cells [Griswold et al. Mol Cell Biol.2006;26(16):6082–93.]. Since BTK has also been implicated in resistance to imatinib [Hofmann et al. Lancet2002;359(9305):481–6] and one study [Feldhahn et al. J Exp Med.2005; 201(11):1837–52] had suggested a role of BTK in Bcr-Abl-induced transformation we decided to test whether BTK may be a critical node in Bcr-Abl transformation and potential drug target in imatinib-resistant Bcr-Abl-positive cells. Results: We depleted BTK in Ba/F3 and 32D cells expressing native and kinase domain (KD) mutant (E255K and T315I) Bcr-Abl, using shRNA. BTK levels were reduced to <10% of controls, but no differences in viability and cell proliferation were observed. Additionally, responses to imatinib were not affected by BTK depletion. We further tested the effects of reversible (PCI-33918) and irreversible (PCI-31523) small molecule inhibitors of BTK on the above cell lines as well as human Ph+ B-lymphoblastic lines. Selective BTK inhibition did not impact cell proliferation. Lastly, BTK inhibition had no effect on Bcr-Abl-mediated transformation of primary murine hematopoietic cells in colony forming assays. Conclusion: Despite the fact the BTK is consistently tyrosine phosophorylated in Bcr-Abl expressing cells, our data suggests it is not essential for Bcr-Abl-mediated transformation of lymphoid or myeloid cells.

scholarly journals Can NF-κB Be Considered a Valid Drug Target in Neoplastic Diseases? Our Point of View

2020 ◽  
Vol 21 (9) ◽  
pp. 3070 ◽  
Author(s):  
Manuela Labbozzetta ◽  
Monica Notarbartolo ◽  
Paola Poma
Keyword(s):  
Myeloid Leukemia ◽  
Drug Target ◽  
Nuclear Factor Kappa B ◽  
Triple Negative ◽  
Scientific Evidence ◽  
Transcriptional Factor ◽  
Point Of View ◽  
Neoplastic Diseases ◽  
Tumor Diseases

Multidrug resistance (MDR), of the innate and acquired types, is one of major problems in treating tumor diseases with a good chance of success. In this review, we examine the key role of nuclear factor-kappa B (NF-κB) to induce MDR in three tumor models characterized precisely by innate or acquired MDR, in particular triple negative breast cancer (TNBC), hepatocellular carcinoma (HCC), and acute myeloid leukemia (AML). We also present different pharmacological approaches that our group have employed to reduce the expression/activation of this transcriptional factor and thus to restore chemo-sensitivity. Finally, we examine the latest scientific evidence found by other groups, the most significant clinical trials regarding NF-κB, and new perspectives on the possibility to consider this transcriptional factor a valid drug target in neoplastic diseases.

scholarly journals DIA-based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid Leukemia

2021 ◽  
Author(s):  
wei liu ◽  
Yaoting Sun ◽  
weigang ge ◽  
fangfei zhang ◽  
lin gan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Drug Target ◽  
Acquired Resistance ◽  
Resistance Index ◽  
K562 Cells ◽  
Resistance Mechanisms ◽  
Acquired Drug Resistance ◽  
Proteome Changes

Drug resistance is a critical obstacle to effective treatment in patients with chronic myeloid leukemia (CML). To understand the underlying resistance mechanisms in response to imatinib (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for two months to generate derivative cells with mild, intermediate and severe resistance to the drugs as defined by their increasing resistance index (RI). PulseDIA-based quantitative proteomics was then employed to reveal the proteome changes in these resistant cells. In total, 7,082 proteotypic proteins from 98,232 peptides were identified and quantified from the dataset using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. Sirtuin Signaling Pathway was found to be significantly enriched in both ADR- and IMA-resistant K562 cells. In particular, IDH2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated IDH2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR.

scholarly journals Possible involvement of a tyrosine kinase-dependent pathway in the regulation of phosphoinositide metabolism by vanadate in normal mouse islets

1996 ◽  
Vol 315 (1) ◽  
pp. 49-55 ◽  
Author(s):  
Jean-Christophe JONAS ◽  
Jean-Claude HENQUIN
Keyword(s):  
Tyrosine Kinases ◽  
Cell Function ◽  
Calf Serum ◽  
Regulatory Subunit ◽  
Phosphoinositide Metabolism ◽  
Sds Page ◽  
Mouse Islets ◽  
Dependent Pathway ◽  
Phosphotyrosine Phosphatases

The potential roles of protein tyrosine kinases (TKs) and of phosphotyrosine phosphatases (PTPs) in pancreatic islet function are not known. In this study, we investigated whether vanadate, a potent PTP inhibitor, affects phosphoinositide (PI) metabolism by a TK-dependent pathway in isolated mouse islets. To avoid the confounding effects of changes in Ca2+ influx, all experiments were performed in the absence of Ca2+. In the presence of 15 mM glucose, vanadate, acetylcholine (ACh) or [Arg]vasopressin (AVP) strongly stimulated InsP production. Vanadate also increased PtdInsP levels in membranes. The TK inhibitor genistein (not its inactive analogues genistin and daidzein) significantly reduced vanadate effects, but was without effect in the absence of stimulation or in the presence of ACh or AVP. Islet proteins resolved by SDS/PAGE were analysed by immunoblotting with anti-phosphotyrosine antibody. Under control conditions, several phosphotyrosyl-proteins (PYPs) were present. Vanadate increased phosphotyrosine residues on several PYPs, notably two proteins of 145 and 85 kDa. This effect was prevented by genistein. p145 and p85 could correspond to phospholipase Cγ (PLCγ) and the regulatory subunit of PtdIns-3-kinase (PtdIns-3K) respectively. Both proteins are expressed in islets, as revealed by immunoblots with specific antibodies. Tungstate, another PTP inhibitor, reproduced vanadate effects, but inhibition of PtdIns-3K by wortmannin failed to affect vanadate-increased PtdInsP levels. Incubation of the islets in the presence of 10% (v/v) fetal calf serum instead of BSA increased InsP production and this effect was prevented by genistein. These results suggest that inhibition of PTP increases InsP production in mouse islets by a TK-dependent pathway. They also provide evidence for a potential role of TK and PTP in pancreatic B-cell function.

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