Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (TK) expressed by immature hematopoietic cells and is important for the normal development of stem cells and the immune system. Mutations of the juxtamembranous and TK domain of the gene are described in 30%-35% of patients with acute myeloid leukemia (AML). These mutations alter the biologic properties of AML and are associated with prognosis. In recent years, there has been an enormous development of potential inhibitors of FLT3 mutations. These substances are now being studied in clinical protocols. The initial trials reveal that, unlike in patients with chronic myeloid leukemia, TK inhibitor (TKI) therapy in AML is more complex. To date, most FLT3 TKIs investigated in clinical studies show a favorable toxicity profile with considerable biologic activity. However, refractory disease and/or the rapid development of resistance toward these new drugs remain major challenges. Strategies to circumvent this unsatisfactory clinical potential of FLT3 TKIs are mainly based on the combination with cytotoxic chemotherapy. Herein, we summarize results from studies using FLT3 TKIs as single agents and report on the first clinical trials investigating FLT3 TKIs in combination with chemotherapy.
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PMID:FLT3 kinase inhibitors in the management of acute myeloid leukemia. 1828 63

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in human gastrointestinal tract. We first found that most GISTs expressed KIT, a receptor tyrosine kinase encoded by protooncogene c-kit and that approximately 90% of the sporadic GISTs had somatic gain-of-function mutations of the c-kit gene. Since both GISTs and interstitial cells of Cajal (ICCs) were double-positive for KIT and CD34, GISTs were considered to originate from ICCs or their precursor cells. We also found that germline gain-of-function mutations of the c-kit gene resulted in familial and multiple GISTs with diffuse hyperplasia of ICCs as the preexisting lesion. Moreover, we found that about half of the sporadic GISTs without c-kit gene mutations had gain-of-function mutations of platelet-derived growth factor receptor alpha (PDGFRA) gene that encodes another receptor tyrosine kinase. Imatinib which is known to inhibit constitutively activated BCR-ABL tyrosine kinase in chronic myelogenous leukemia also inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for metastatic or unresectable GISTs as a molecular target drug. Mutational analyses of c-kit and PDGFRA genes are considered to be significant for prediction of effectiveness of imatinib and newly developed/developing other agents on GISTs. Some mouse models of familial and multiple GISTs have been genetically created, and may be useful for further investigation of GIST biology.
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PMID:Gain-of-Function Mutations of Receptor Tyrosine Kinases in Gastrointestinal Stromal Tumors. 1836 5

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The name "GIST" was proposed in 1983, but the cell origin of GIST remained unclear until 1998, when my colleagues and I reported immunohistochemical evidence that GIST originated from interstitial cells of Cajal or their precursors. At the same time, we reported gain-of-function mutations of the Kit gene in GISTs. The Kit gene encodes KIT receptor tyrosine kinase, whose structure is similar to that of platelet-derived growth factor receptor (PDGFR). Imatinib mesylate was initially developed as an inhibitor of PDGFR. Then, it was found to be a potent inhibitor of BCR-ABL. Imatinib was successfully used for the treatment of chronic myeloid leukemia. When we reported gain-of-function mutations of the Kit gene in GISTs, the inhibitory effect of imatinib on KIT was already known. Imatinib was then successfully applied to the treatment of GISTs. The interrelationship between the type of Kit gain-of-function mutation and the therapeutic effect of imatinib has been well characterized in GISTs. Although various mutations of Kit and Pdgfr-alpha genes have been found in GISTs, most GISTs are luckily imatinibsensitive. After long-term administration of imatinib, however, new imatinib-resistant clones develop a secondary mutation of the Kit or Pdgfr-alpha gene. New drugs and adjuvant regimens against such secondary progression are now being intensively explored.
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PMID:Gastrointestinal stromal tumors: past, present, and future. 1864 36

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder caused by increased and unregulated growth of myeloid cells in the bone marrow, and the accumulation of excessive white blood cells. Abelson tyrosine kinase (ABL) is a non-receptor tyrosine kinase involved in cell growth and proliferation and is usually under tight control. However, 95% of CML patients have the ABL gene from chromosome 9 fused with the breakpoint cluster (BCR) gene from chromosome 22, resulting in a short chromosome known as the Philadelphia chromosome. This Philadelphia chromosome is responsible for the production of BCR-ABL, a constitutively active tyrosine kinase that causes uncontrolled cellular proliferation. An ABL inhibitor, imatinib, was approved by the FDA for the treatment of CML, and is currently used as first line therapy. However, a high percentage of clinical relapse has been observed due to long term treatment with imatinib. A majority of these relapsed patients have several point mutations at and around the ATP binding pocket of the ABL kinase domain in BCR-ABL. In order to address the resistance of mutated BCR-ABL to imatinib, 2(nd) generation inhibitors such as dasatinib, and nilotinib were developed. These compounds were approved for the treatment of CML patients who are resistant to imatinib. All of the BCR-ABL mutants are inhibited by the 2(nd) generation inhibitors with the exception of the T315I mutant. Several 3(rd) generation inhibitors such as AP24534, VX-680 (MK-0457), PHA-739358, PPY-A, XL-228, SGX-70393, FTY720 and TG101113 are being developed to target the T315I mutation. The early results from these compounds are encouraging and it is anticipated that physicians will have additional drugs at their disposal for the treatment of patients with the mutated BCR-ABL-T315I. The success of these inhibitors has greater implication not only in CML, but also in other diseases driven by kinases where the mutated gatekeeper residue plays a major role.
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PMID:Inhibitors of ABL and the ABL-T315I mutation. 1867 74

Imatinib, nilotinib and dasatinib are protein kinase inhibitors which target the tyrosine kinase activity of the Breakpoint Cluster Region-Abelson kinase (BCR-ABL) and are used to treat chronic myelogenous leukemia. Recently, using a chemical proteomics approach another tyrosine kinase, the collagen receptor Discoidin Domain Receptor1 (DDR1) has also been identified as a potential target of these compounds. To further investigate the interaction of imatinib, nilotinib and dasatinib with DDR1 kinase we cloned and expressed human DDR1 and developed biochemical and cellular functional assays to assess their activity against DDR1 and the related receptor tyrosine kinase Discoidin Domain Receptor2 (DDR2). Our studies demonstrate that all 3 compounds are potent inhibitors of the kinase activity of both DDR1 and DDR2. In order to investigate the question of selectivity among DDR1, DDR2 and other tyrosine kinases we have aligned DDR1 and DDR2 protein sequences to other closely related members of the receptor tyrosine kinase family such as Muscle Specific Kinase (MUSK), insulin receptor (INSR), Abelson kinase (c-ABL), and the stem cell factor receptor (c-KIT) and have built homology models for the DDR1 and DDR2 kinase domains. In spite of high similarity among these kinases we show that there are differences within the ATP-phosphate binding loop (P-loop), which could be exploited to obtain kinase selective compounds. Furthermore, the potent DDR1 and DDR2 inhibitory activity of imatinib, nilotinib and dasatinib may have therapeutic implications in a number of inflammatory, fibrotic and neoplastic diseases.
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PMID:Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. 1893 56

Hair depigmentation has been shown to occur with disruption of the interaction between the ligand stem cell factor (SCF) with its class III receptor tyrosine kinase c-kit, also called the stem cell factor receptor. This article reports the case of a patient who experienced depigmentation of her eyelashes, eyebrows, and temporal scalp hair six-to-eight weeks after initiating treatment with dasatinib (BMS-354825 or Sprycel), a novel dual Bcr-Abl/Src family tyrosine kinase inhibitor for chronic myeloid leukemia (CML). This case illustrates a previously unreported side-effect of dasatinib that is most likely due to the drug's inhibition of the c-kit, Src family, and platelet-derived growth factor receptor beta (PDGFRbeta) tyrosine kinases. Further study of hair depigmentation as a side effect of multi-kinase inhibitors can provide useful information on hair and melanocyte physiology.
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PMID:Hair depigmentation during chemotherapy with dasatinib, a dual Bcr-Abl/Src family tyrosine kinase inhibitor. 1936 59

This review analyzes the state of the art of targeted therapies for several tumors, starting from the paradigmatic example of Imatinib treatment in chronic myelogenous leukemia (CML). We discuss how rare tumors can be models for various mechanisms of receptor tyrosine kinase (RTK) activation, and provide the opportunity to develop new therapies also for more common cancer types. We discuss the activation of the downstream RTK effectors as further targets for therapies in colorectal cancer. Finally, we highlight how a novel multidimensional approach which adds an in silico dimension to the in vitro and in vivo approach, can predict clinical results.
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PMID:Targeted therapies: the rare cancer paradigm. 1991 65

Myeloid zinc finger 1 (MZF1) is a member of the SCAN domain family transcription factors that form dimers through their highly conserved SCAN motifs. Silencing of MZF1 inhibits cell proliferation, and abnormal expression of MZF1 results in cancer development. However, a potential role of MZF1 in metastasis remains unclear. Axl is a receptor tyrosine kinase and was first identified as a transforming gene in chronic myeloid leukemia. Axl overexpression induces proliferation, migration, and invasion and is highly expressed in different human cancers. In this study, we show that overexpression of MZF1 induces migration and invasion in colorectal (Rko, SW480) and cervical (HeLa) cancer cells. In addition, we show that MZF1 binds to the Axl promoter, transactivates promoter activity, and enhances Axl-mRNA and protein expression in a dose-dependent manner. In vitro, sh-RNA knockdown of Axl reduced MZF1-induced migration and invasion in HeLa and Rko cells (P = 0.05). Additionally, Rko cells overexpressing MZF1 showed increased tumor formation and liver metastasis in the chicken-embryo-metastasis assay in vivo. Furthermore, the expression of MZF1 and Axl was significantly higher in resected colorectal tumors compared with corresponding normal tissues (P = 0.02; P = 0.05), and MZF1 expression was positively correlated with Axl gene expression in tumor tissues (P < 0.01). Taken together, this is the first study to show that MZF1 induces invasion and in vivo metastasis in colorectal and cervical cancer, at least in part by regulating Axl gene expression.
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PMID:Myeloid zinc finger 1 induces migration, invasion, and in vivo metastasis through Axl gene expression in solid cancer. 2014 42

The development of the so-called "targeted therapies", particularly those drugs that inhibit the activity of tyrosine kinases, has become a remarkable progress in the treatment of neoplastic diseases. The small molecule tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of chronic myeloid leukemia, and trastuzumab, the humanized monoclonal antibody against the ERBB2 receptor tyrosine kinase, has proved to have a high efficacy in 25% of breast cancers. On the basis of treatment success it is expected that targeted therapies will spread its use in the future. Recent data has shown that some of these therapies are associated with certain cardiotoxicity ranging from asymptomatic mild left ventricular dysfunction to congestive heart failure through different mechanisms. However, rates of cardiotoxicity associated with TKI are not well known mainly because clinical trials usually do not include predefined cardiac endpoints or the assessment of left ventricular function before and during treatment. In addition, it is especially difficult to diagnose heart failure in patients with some kinds of cancer who have many reasons to develop dyspnoea. Here we summarize what is known up to date about the cardiotoxicity of drugs targeting the tyrosine kinases. Being aware of the risk of using these drugs is particularly important to early detect and institute the appropriate treatment to prevent irreversible myocardial injury, especially when some neoplastic diseases, as haematological or breast cancers, can affect to young people with an estimated long-term survival.
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PMID:Cardiotoxicity of tyrosine-kinase-targeting drugs. 2021 Jul 73

c-Kit is a receptor tyrosine kinase (RTK) with a pivotal role in melanogenesis, gametogenesis, and hematopoiesis. Aberrantly activated RTK and related downstream signaling partners were identified as key elements in the molecular pathogenesis of several malignancies. This finding culminated in a two-class model integrating constitutive activating and maturation arrest-inducing mutations as key elements for the pathogenesis of acute myelogenous leukemia (AML). c-Kit is expressed by myeloblasts in about 60% to 80% of patients, and the most frequently observed activating RTK mutations in AML (next to FLT3) are mutations or internal tandem duplications in c-Kit, with an overall incidence of 17%. The identification of small-molecule tyrosine kinase inhibitors capable of blocking key kinase switches introduced a paradigm change in the treatment of diseases like gastrointestinal stromal tumors and chronic myelogenous leukemia. Despite encouraging preclinical data, it appears that a complex clonal disease like AML will probably benefit from a synergistic approach of targeted drugs used (at least for now) in combination with conventional chemotherapy.
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PMID:Clinical implications of c-Kit mutations in acute myelogenous leukemia. 2042 18


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