Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

c-kit, a growth factor receptor with tyrosine kinase activity, plays an important role in the biology of cancer. Its expression has been documented in several malignancies. We performed a retrospective study in 85 patients diagnosed with small cell lung cancer (SCLC) to determine the prevalence and role of c-kit as a possible prognostic marker in this lung cancer malignancy. Demographic and clinical data were obtained from patient charts. c-kit, analyzed as immunohistochemical expression in paraffin-embedded tumour tissues, was observed in 60% of patients. All patients were former or present smokers. At diagnosis, 46% of the patients had limited disease (LD) and 54% extended disease (ED). c-kit expression was observed in 59% of LD and 61% of ED patients (p=0.4). Patients received a median of 4 cycles first-line combination chemotherapy (platinum and etoposide). In LD patients, time to progression (TTP) was 11.5 months in c-kit (+) versus 5.9 in c-kit (-) patients (p=0.14), and median survival 15.4 and 12.8 months, respectively (p=0.33). In the ED group, TTP was 5.5 months in c-kit (+) versus 3.8 in c-kit (-) patients (p=0.34), whereas median survival was 6.3 and 7.9 months, respectively (p=0.45). With the limited number of patients in mind, our findings tended towards an association between c-kit expression and survival in the LD group.
Lung Cancer 2006 Jun
PMID:Analysis of c-kit expression in small cell lung cancer: prevalence and prognostic implications. 1657 70

In non-small-cell lung cancer (NSCLC), stage of the disease is still the most important prognostic factor. Other than stage, many biological markers and many other prognostic factors are studied to define their effects on prognosis of lung cancer. In this study, we aimed to evaluate the expressions of Bax and bcl-2 genes which are important in apoptosis and c-kit, which is a tyrosine kinase transmembrane receptor, as well as searched their response to treatment modalities and effects on survival. Sixty-nine NSCLC cases' pathological samples were stained with specific Bax, bcl-2 and c-kit dyes by immunohistochemical (IHC) methods. IHC evaluation was done by the semichantitative method according to the distribution and intensity of the staining. Twelve of 69 cases (17.4%) were stage I, 28 (40.5%) were stage II, 17 were (24.6%) stage IIIA, nine cases were (13.1%) stage IIIB and three cases (4.4%) were stage IV patients. Their histological subtypes were as follows: of 69 cases, 36 (52.2%) were squamous cell carcinoma, 28 (40.6%) were adenocarcinoma, five (7.2%) were adenosquamous cell carcinoma (two patients) and large-cell carcinoma (three patients). The positive immunostaining rates for Bax and bcl-2 in whole group, squamous cell carcinoma and adenocarcinoma groups were 40.6%/36.2%, 55.6/69.4% and 25.0/0.0%, respectively. The positive immune staining rates for c-kit in whole group, squamous cell carcinoma and adenocarcinoma groups were 7.2, 5.6 and 7.1%, respectively. We didn't find any correlation with Bax, bcl-2 and c-kit expressions and clinicopathological parameters such as age, tumour size, lymph node involvement, smoking, stage of the disease, response to radiotherapy and chemotherapy. Results are interpreted according to survival; bax and bcl-2 expressions were not so effective both in whole group and histologically subgrouped patients. C-kit expression was also found not related with survival in whole group whereas found as a bad prognostic factor in patients with squamous cell carcinoma. These findings could indicate that the expression of apoptotic pathway markers and c-kit may have a role in the prognosis of early stage NSCLC, especially with squamous cell carcinoma subtype.
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PMID:Bax, bcl-2 and c-kit expression in non-small-cell lung cancer and their effects on prognosis. 1680 52

Small cell lung cancer (SCLC) is an aggressive form of lung cancer, which represents 13% of all cases and is strongly associated with cigarette smoking. The survival of SCLC patients is dismal and has not greatly improved in the last 20 years, despite advances in chemotherapy regimens and a better understanding of SCLC biology. The development of resistance to chemotherapy and metastasis are commonly recognized as important causes of poor clinical outcome in SCLC. Targeting receptor tyrosine kinase (RTK) signalling represents an attractive approach to develop new drugs for SCLC, in view of the accumulating data demonstrating that polypeptide growth factors play a key role in driving SCLC cell proliferation, chemoresistance and metastasis. The insulin-like growth factor-I receptor (IGF-IR), c-Kit, vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) have been identified as potential drug targets in SCLC. Moreover, downstream signalling mediators of RTKs, such as phosphoinositide 3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) may also represent attractive candidate molecules for anti-cancer therapies in SCLC. Here we will review the available data concerning results with RTK inhibitors in SCLC and the clinical trials undertaken to investigate the potential of these compounds as anti-tumour agents in SCLC.
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PMID:Targeting receptor tyrosine kinase signalling in small cell lung cancer (SCLC): what have we learned so far? 1736 33

SU11248 sunitinib malate sutent is a selective inhibitor of certain protein tyrosine kinases including VEGF-R types 1-3 PDGF-R-a and -b, c-kit, and RET. Its antitumor activity may result from both inhibition of angiogenesis and direct antiproliferative effects on certain tumor types. In several phase I/II/III studies, sutent was found to be effective as second and first line treatment in metastatic renal cell carcinoma (RCC). In fact, with a 37% response rate and an additional 48% stable disease sutent became the drug of choice for first line treatment in RCC. Sutent was also effective as second line treatment in patients with gastrointestinal stromal tumors (GIST) with 8% response rate, 70% stable disease and a 20-month median survival. Prolonged stable disease was also documented in neuroendocrine tumors. In addition, a phase II study in multitreated women with breast cancer, sutent demonstrated a moderate activity with 16% clinical benefit. Finally, in non-small cell lung cancer (NSCLC) in patients' progressing on chemotherapy sutent was able to achieve a 10% response rate, a level of activity similar to those documented by other agents approved for lung cancer. The agent is being tested in other tumors with a modified schedule of dosage.
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PMID:Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma and various other solid tumors. 1794 82

FUS1 is a novel tumor suppressor gene identified in the human chromosome 3p21.3 region where allele losses and genetic alterations occur early and frequently for many human cancers. Expression of FUS1 protein is absent or reduced in the majority of lung cancers and premalignant lung lesions. Restoration of wt-FUS1 function in 3p21.3-deficient non-small cell lung carcinoma cells significantly inhibits tumor cell growth by induction of apoptosis and alteration of cell cycle kinetics. Here we present recent findings indicating that FUS1 induces apoptosis through the activation of the intrinsic mitochondrial-dependent and Apaf-1-associated pathways and inhibits the function of protein tyrosine kinases including EGFR, PDGFR, AKT, c-Abl, and c-Kit. Intravenous administration of a nanoparticle encapsulated FUS1 expression plasmid effectively delivers FUS1 to distant tumor sites and mediates an antitumor effect in orthotopic human lung cancer xenograft models. This approach is the rationale for an ongoing FUS1-nanoparticle-mediated gene delivery clinical trial for the treatment of lung cancer.
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PMID:Tumor suppressor FUS1 signaling pathway. 1837 48

Pazopanib, which is being developed by GlaxoSmithKline plc, is an oral, second-generation multi-targeted tyrosine kinase inhibitor that targets VEGFR, platelet-derived growth factor receptor and c-kit, key proteins responsible for tumor growth and survival. Pazopanib exhibited good potency against all of the human VEGFRs and closely related tyrosine receptor kinases in vitro, and demonstrated antitumor activity in several human tumor xenografts, including renal cell carcinoma (RCC), and breast and lung cancer. In phase I and II clinical trials, pazopanib was generally well tolerated with the main side effects being hypertension, fatigue or gastrointestinal disorders. Pazopanib alone caused a decrease in tumor size and stable disease in a significant number of patients, including those with RCC, NSCLC and gynecological tumors. The combination of pazopanib with lapatinib was effective in patients with breast cancer. At the time of publication, pazopanib monotherapy was being evaluated in phase III trials in patients with RCC and as combination therapy with lapatinib in patients with breast cancer. In addition, phase I and II trials were being conducted to assess pazopanib alone or in combination with a range of chemotherapeutics in patients with solid tumors or multiple myeloma.
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PMID:Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. 1903 39

Pazopanib and lapatinib are two tyrosine kinase inhibitors that have been designed to inhibit the VEGF tyrosine kinase receptors 1, 2 and 3 (pazopanib), and the HER1 and HER2 receptors in a dual manner (lapatinib). Pazopanib has also been reported to mediate inhibitory effect on a selected panel of additional tyrosine kinases such as PDGFR and c-kit. Here, we report that pazopanib and lapatinib act synergistically to induce apoptosis of A549 non-small-cell lung cancer cells. Systematic assessment of the kinome revealed that both pazopanib and lapatinib inhibited dozens of different tyrosine kinases and that their combination could suppress the activity of some tyrosine kinases (such as c-Met) that were not or only partially affected by either of the two agents alone. We also found that pazopanib and lapatinib induced selective changes in the transcriptome of A549 cells, some of which were specific for the combination of both agents. Analysis of a panel of unrelated human carcinoma cell lines revealed a signature of 52 genes whose up- or downregulation reflected the combined action of pazopanib and lapatinib. Indeed, pazopanib and lapatinib exerted synergistic cytotoxic effects on several distinct non-small-cell lung cancer cells as well as on unrelated carcinomas. Altogether, these results support the contention that combinations of tyrosine kinase inhibitors should be evaluated for synergistic antitumor effects. Such combinations may lead to a 'collapse' of pro-survival signal transduction pathways that leads to apoptotic cell death.
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PMID:Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines. 1974 98

Sunitinib is an orally available small-molecule multikinase inhibitor. This agent potently inhibits the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit in addition to other kinases in biochemical and cell-based assays. In several relevant preclinical cancer models, sunitinib exerts significant antiangiogenesis and antitumor effects. In phase I studies, using intermittent dosing schedules, oral administration of doses up to 50 mg/day were reasonably well tolerated and resulted in plasma concentrations in the range of targeted levels needed for sustained kinase inhibition. Biomarker and functional imaging studies showed modulation of circulating markers of angiogenesis as well as a reduction in tumor metabolism. Sunitinib showed clinical activity in patients with renal cell cancer and in patients with imatinib-resistant gastrointestinal stromal tumors. Definitive randomized clinical trials showed significant clinical activity in these two indications leading to regulatory approval. In addition, this drug has showed activity in a variety of other tumor types such as breast, colon, and lung cancer and is being explored in combination with standard drugs in these diseases. The observation that biological and functional imaging effects are reduced during drug-free intervals has prompted the evaluation of protracted dosing schedules. A better understanding of mechanisms involved in resistance to sunitinib provides the rationale for combination strategies that hopefully will result in better clinical effect. Ongoing studies will elucidate the overall role of this drug in cancer treatment.
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PMID:Understanding the molecular-based mechanism of action of the tyrosine kinase inhibitor: sunitinib. 2011 Jul 85

Despite significant efforts in diagnosing and treating lung cancer, therapeutic resistance remains a major unresolved clinical and scientific problem. Cancer stem cells (CSCs) are thought to be responsible for the failure of current chemotherapy of lung cancer. The concept of CSCs has radically changed the view of cancer therapy. Today a majority of current treatment modalities target the differentiated cancer cells and avoid the drug resistant cancer-initiating stem cells. This review summarizes our understanding of lung CSCs and their role in metastasis formation and growth of non- small-cells lung cancer (NSCLC). High tumorigenic and metastatic properties of lung CSCs are associated with the efficient cytokine network production and with the specific signaling pathways. This review underlines the experimental evidence indicating that the stem cell factor (SCF) and its receptor c-kit (CD117) play an important role in survival and proliferation of lung CSCs. Thus, molecularly targeting key cytokine network axes of such highly tumorigenic and metastatic CSCs must be considered for improving the current anti-cancer strategy efficacy. Standard chemotherapy in combination with specific axis of cytokine network targeting, such as SCF-c-kit, could eliminate both bulk tumor cells and CSCs, and therefore to be truly curative therapies. This review provides a summary of some of the developments in the field of lung CSCs targeting and highlights aspects which could help in the drug discovery process.
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PMID:Lung cancer stem cells as a target for therapy. 2018 38

Lung cancer is the leading cause of cancer-related mortality worldwide and more than 1 million people annually die in consequence of lung cancer. Although an improvement in lung cancer treatment could be achieved, especially in the last decade, the development of additional therapeutic strategies is urgently required in order to provide improved survival benefit for patients. Lung cancer formation is caused by genetic modifications commonly caused by tobacco smoking. Numerous studies have demonstrated the role of extracellular growth factors in lung cancer cell proliferation, metastasis, and chemoresistance. Mutations and amplifications in molecules related to receptor tyrosine signalling, such as EGFR, ErbB2, c-Met, c-Kit, VEGFR, PI3K, and PTEN are only some of the alterations known to contribute to the development of lung cancer. The phosphoinositide 3-kinase (PI3K) pathway, fundamental for cell development, growth, and survival, is known to be frequently altered in neoplasia, including carcinomas of the lung. Based on the high frequency of alterations, which include mutations and amplifications, leading to over-activation of certain upstream/downstream mediators, targeting components of the PI3K signalling pathway is considered to be a promising therapeutic approach in cancer treatment. In this article we will summarize the current knowledge about the involvement of PI3K signalling in lung cancer and discuss the development of targeted therapies involving PI3K pathway inhibitors.
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PMID:Targeting phosphoinositide 3-kinase signalling in lung cancer. 2131 60


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