Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD117 (KIT) is a type III receptor tyrosine kinase operating in cell signal transduction in several cell types. Normally KIT is activated (phosphorylated) by binding of its ligand, the stem cell factor. This leads to a phosphorylation cascade ultimately activating various transcription factors in different cell types. Such activation regulates apoptosis, cell differentiation, proliferation, chemotaxis, and cell adhesion. KIT-dependent cell types include mast cells, some hematopoietic stem cells, germ cells, melanocytes, and Cajal cells of the gastrointestinal tract, and neoplasms of these cells are examples of KIT-positive tumors. Other KIT-positive normal cells include epithelial cells in skin adnexa, breast, and subsets of cerebellar neurons. KIT positivity has been variably reported in sarcomas such as angiosarcoma, Ewing sarcoma, synovial sarcoma, leiomyosarcoma, and MFH; results of the last three are controversial. The variations in published data may result from incomplete specificity of some polyclonal antibodies, possibly contributed by too high dilutions. Also, KIT is expressed in pulmonary and other small cell carcinomas, adenoid cystic carcinoma, renal chromophobe carcinoma, thymic, and some ovarian and few breast carcinomas. A good KIT antibody reacts with known KIT positive cells, and smooth muscle cells and fibroblasts are negative. KIT deficiency due to hereditary nonsense/missense mutations leads to disruption of KIT-dependent functions such as erythropoiesis, skin pigmentation, fertility, and gastrointestinal motility. Conversely, pathologic activation of KIT through gain-of-function mutations leads to neoplasia of KIT-dependent and KIT-positive cell types at least in three different systems: mast cells/myeloid cells--mastocytosis/acute myeloid leukemia, germ cells--seminoma, and Cajal cells--gastrointestinal stromal tumors (GISTs). KIT tyrosine kinase inhibitors such as imatinib mesylate are the generally accepted treatment of metastatic GISTs, and their availability has prompted an active search for other treatment targets among KIT-positive tumors such as myeloid leukemias and small cell carcinoma of the lung, with variable and often nonconvincing results.
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PMID:KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. 1608 45

Imatinib mesylate (IM), is a selective and competitive inhibitor of tyrosine kinases, including BCR-ABL, ABL, KIT, and the platelet-derived growth factor receptors (PDGF-R). It binds to the ATP-binding site of the target kinase and prevents the transfer of phosphate from ATP to the tyrosine residues of various substrates. At oral doses of 200-600 mg, the majority of patients with chronic myeloid leukaemia, Philadelphia chromosome-positive acute lymphoblastic leukemia expressing the BCR-ABL fusion protein and gastrointestinal stromal tumours (GIST) achieve a bio-molecular and clinical response, frequently complete, associated with limited toxicity. Several other human cancers, as small-cell lung carcinoma, melanoma, seminoma, some sarcomas, and adenoid cystic carcinomas may over-express KIT or PDGF-R, and clinical trials to evaluate the role of IM in the treatment of such cancers are currently ongoing. We determined c-KIT with Dako CD 117 antibody in 5 cases of advanced ocular melanoma (OM) and we found positive immuno-reactivity for CD 117 in three patients. We treated all patients with palliative-use IM at the oral dose of 400 mgr daily. We obtained in expressing positive immuno-reactivity for CD 117 patients: a reduction of malignant ascites in one, a partial remission in the neck nodes in another, and progression of liver metastases in the third. Evidences of progression has been reported in the other two patients expressing negative immuno-reactivity for CD 117. We conclude that the effect of IM should be assessed only in OM with positive immuno-histochemical c-kit (CD 117) expression. IM might be a potential therapeutic strategy for these patients.
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PMID:Tyrosine kinase inhibitor imatinib mesylate as anticancer agent for advanced ocular melanoma expressing immunoistochemical C-KIT (CD 117): preliminary results of a compassionate use clinical trial. 1676

This review is focused on "new drugs" that might be developed for thyroid cancer treatment. Thyroid cancer is frequently associated to the activation of specific protein (RET, BRAF) and lipid [PI(3)K] kinases. There is good evidence that these genetic lesions are causative events in thyroid cancer initiation or progression. Therefore, novel compounds able to target these kinases might be useful for thyroid cancer treatment. The power of this approach is witnessed by the examples of BCR-ABL, c-KIT and EGFR inhibitors in the treatment of chronic myelogenous leukemia (CML), gastro-intestinal stromal tumors (GIST) and non-small cell lung carcinoma (NSCLC).
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PMID:New drugs in thyroid cancer. 1789 Dec 51

E7080 is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. In this study, we show the inhibitory activity of E7080 against SCF-induced angiogenesis in vitro and tumor growth of SCF-producing human small cell lung carcinoma H146 cells in vivo. E7080 inhibits SCF-driven tube formation of HUVEC, which express SCF receptor, KIT at the IC(50) value of 5.2 nM and it was almost identical for VEGF-driven one (IC(50) = 5.1 nM). To assess the role of SCF/KIT signaling in tumor angiogenesis, we evaluated the effect of imatinib, a selective KIT kinase inhibitor, on tumor growth of H146 cells in nude mice. Imatinib did not show the potent antitumor activity in vitro (IC(50) = 2,200 nM), because H146 cells did not express KIT. However, oral administration of imatinib at 160 mg/kg clearly slowed tumor growth of H146 cells in nude mice, accompanied by decreased microvessel density. Oral administration of E7080 inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg. While anti-VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCF-producing H146 cells, and E7080 causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling. E7080 may provide therapeutic benefits in the treatment of SCF-producing tumors.
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PMID:E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. 1794 26

This study was conducted to evaluate the prevalence of EGFR and KIT mutations in thymomas and thymic carcinomas as a means of exploring the potential for molecularly targeted therapy with tyrosine kinase inhibitors. Genomic DNA was isolated from 41 paraffin-embedded tumor samples obtained from 24 thymomas and 17 thymic carcinomas. EGFR exons 18, 19, and 21, and KIT exons 9, 11, 13, and 17, were analyzed for mutations by PCR and direct sequencing. Protein expression of EGFR and KIT was evaluated immunohistochemically. EGFR mutations were detected in 2 of 20 thymomas, but not in any of the thymic carcinomas. All of the EGFR mutations detected were missense mutations (L858R and G863D) in exon 21. EGFR protein was expressed in 71% of the thymomas and 53% of the thymic carcinomas. The mutational analysis of KIT revealed only a missense mutation (L576P) in exon 11 of one thymic carcinoma. KIT protein was expressed in 88% of the thymic carcinomas and 0% of the thymomas. The results of this study indicate that EGFR and KIT mutations in thymomas and thymic carcinomas are rare, but that many of the tumors express EGFR or KIT protein.
Lung Cancer 2008 Dec
PMID:Mutational status of EGFR and KIT in thymoma and thymic carcinoma. 1844 88

The author reports a very rare case of cutaneous metastasis of sarcomatoid carcinoma of the lung. The skin metastasis was an initial presentation. A 67-year-old man consulted our hospital because of left chest skin mass. An excisional biopsy was performed, and it showed proliferation of malignant sarcomatoid spindle and polygonal cells in the deep dermis and subcutis remote from the epidermis and appendages. Immunohistochemically, the tumor cells were positive for pancytokeratins, cytokeratin (CK) 7, CK 18, vimentin, p53, Ki-67 (95%) and PDGFRA. They were negative for high molecular weight CK, CK 5/6, CK 14, CK 19, CK 20, epithelial membrane antigen, TTF-1, CEA, desmin, S100 protein, alpha-smooth muscle actin, p63, CD34, surfactant apoprotein A, chromogranin, synaptophysin, neuron-specific enolase, CD68, CD56, D2-40, calretinin and KIT. A pathological diagnosis of metastatic sarcomatoid carcinoma probably originating from the lung was made. Then, the patient was admitted to our hospital, and imaging modalities including computed tomography (CT) and magnetic resonance imaging (MRI) revealed a tumor in the left lung. No other tumors were detected in the imaging techniques. Lung biopsy was planned, but the patient suddenly died; the cause of death was unclear. Autopsy was not performed. The present report suggests that sarcomatoid carcinoma of the lung should be considered in cutaneous metastatic lesions.
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PMID:Sarcomatoid carcinoma of the lung presenting as a cutaneous metastasis. 1960 61

The author reports herein a case of occult very small lung carcinoma with a solitary brain metastasis that is clinically diagnosed as cavernous hemangioma, with an emphasis on pathologic findings. A 48-year-old Japanese man was admitted to our hospital complaining of mild paresis of left leg. Brain CT and MRI showed a solitary tumor (2 cm) with features of cavernous hemangioma in the right temporal lobe. Tumorectomy was performed, and it was pathologically undifferentiated carcinoma. An immunohistochemical analysis reveled that the carcinoma cells were positive for four types of pancytokeratin, cytokeratin (CK) 5/6, CK7, CK18, CK19, p63, and Ki-67 (78%). They were negative for high molecular weight CK, CK14, CK20, TTF-1, PE-10, melanosome, S100 protein, EMA, vimentin, CD34, myoglobin, CEA, p53, desmin, alpha-smooth muscle actin, chromogranin, synaptophysin, CD56, neuron-specific enolase, CD68, KIT, and PDGFRA. The positive CK7 and negative CK20 suggested lung origin, and cytokeratin profiles and positive CK5/6 and p63 suggested a squamous differentiation. The pathological diagnosis was undifferentiated carcinoma with squamous differentiation probably of lung origin. Later, systemic CT, MRI and PET were performed, and they detected a small lung tumor (8 mm) in the right apex. The lung biopsy revealed an undifferentiated carcinoma with focal squamous differentiation; the immunohistochemical findings were the same as those of the brain tumor. These findings suggest that occult very small lung carcinoma can metastasize to brain and such a metastasis may mimic cavernous hemangioma radiologically. Pathologic observations using many antibodies are very useful to determine the origin and histological type in solitary brain nodule.
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PMID:Occult very small lung carcinoma with a solitary brain metastasis that is clinically diagnosed as cavernous hemangioma: a case report. 1982 73

The author reports herein a case of small cell carcinoma of the brain without extracranial tumors by serial imaging modalities. A 75-year-old man presented with headache. Brain CT and MRI revealed a solitary cystic tumor (5 x 6 x 7 cm) in the left occipital lobe. Blood laboratory test revealed no significant findings. Preoperative diagnosis was a primary or metastatic brain tumor. Preoperative systemic examinations including CT, MRI and PET revealed no extracranial tumors. Tumorectomy was performed. Pathologically, the tumor was small cell carcinoma positive for four types of pancytokeratins, cytokeratin (CK) 7, CK 18, thyroid transcriptional factor-1 (TTF-1), CD56, chromogranin, synaptophysin, neuron-specific enolase, p53 protein, KIT, PDGFRA, and Ki-67 antigen (labeling = 100%). It was negative for high molecular weight CK, CK5/6, CK14, CK19, CK20, PE10, epithelial membrane antigen, vimentin, CEA, desmin, S100 protein, CA19-9, alpha-smooth muscle actin, CD34, p63, and CD68. The pathologic examination strongly suggested primary small cell lung carcinoma. However, repeated serial imaging modalities including systemic CT, MRI and PET revealed no extracranial tumors. The serial sputum cytology was always negative. The patient was treated with radiation and cisplatin-based chemotherapy, and no tumors were found seven months after the operation. The present case suggests that there are small cell carcinomas with a solitary brain metastasis without a radiologically detected primary site. In the present case, primary small cell brain carcinoma cannot be excluded completely, although such a case has not been reported in the literature.
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PMID:Small cell carcinoma of the brain without extracranial involvement by serial CT, MRI and PET. 2022 32

KIT and PDGFRA in small cell lung carcinoma (SCLC) have been rarely examined in Japanese. The author investigated protein expression of KIT and PDGFRA in 54 Japanese cases of small cell lung carcinoma by immunohistochemistry, and gene mutations of KIT and PDGFRA in 20 Japanese cases of small cell lung carcinoma by the PCR-direct sequencing method. The molecular genetic analysis showed no mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) genes in all 20 cases. KIT protein expression was recognized in all cases (100%). Membranous KIT expression was strong in 35 cases, moderate in 7 cases and weak in 12 cases. PDGFRA protein expression was noted in 35 cases (65%); the membranous expression was strong in 2 cases, moderate in 16 cases, and weak in 17 cases. The overall median survival was 13 months. There was no significant difference in the survival between KIT strongly positive cases (median, 12 months) and KIT moderately or weakly positive cases (median, 11 months). Likewise, there was no significant difference in the survival between PDGFRA-positive cases (median, 11 months) and PDGFRA-negative cases (median, 12 months). The protein expressions of KIT and PDGFRA did not correlate with gender, smoking, and disease stage. These findings suggest, in Japanese population, that mutations of KIT and PDGFRA were absent in small cell lung carcinoma of Japan, that KIT protein expression is present in 100%, that PDGFRA expression is present in 65%, and that KIT and PDGFRA protein expressions do not correlate with survival, gender, smoking, and disease stage.
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PMID:An immunohistochemical and molecular genetic analysis of KIT and PDGFRA in small cell lung carcinoma in Japanese. 2267 Jan 77

The prognosis for patients with large-cell neuroendocrine carcinoma (LCNEC) of the lung is extremely poor, and an optimal treatment has not yet been established. It has been recently reported that molecular-targeted therapies, such as tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR), are effective in patients with lung carcinoma. In efforts to improve the prognosis of patients with LCNEC, we analyzed gene expression, gene mutations and immunohistochemical (IHC) expression of known molecular targets in LCNECs, and compared the expression to that of lung adenocarcinomas (ACs). Thirteen patients with primary LCNEC and 14 patients with AC were analyzed. We evaluated IHC expression for c-KIT, human epidermal growth factor receptor type 2 (HER2) and vascular endothelial growth factor (VEGF), gene mutations for EGFR, K-ras and c-kit, and gene expression using fluorescence in situ hybridization for EGFR. In cases with LCNEC, the IHC expression of c-KIT, HER2 and VEGF was 76.9, 30.8 and 100%, respectively. There was a significant difference in the IHC expression of c-KIT and HER2 between the LCNEC and AC cases. Two cases of LCNEC had overexpression of HER2, and the frequency of EGFR gene mutations was higher in the the AC group, with only a single EGFR mutation (exon 18) identified in the LCNEC group. Although LCNEC had a higher rate of expression of c-KIT by IHC, no c-kit gene mutations were found. These findings suggest a potential role for anti-VEGF-, anti-c-KIT- and possibly anti-HER2-targeted agents in the treatment of LCNEC.
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PMID:Expression profiling and identification of potential molecular targets for therapy in pulmonary large-cell neuroendocrine carcinoma. 2297 17


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