Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epithelial and endothelial tyrosine kinase (Etk), also known as Bmx (bone marrow X kinase), plays an important role in the apoptosis of epithelial cells. The aim of this study was to investigate whether Etk is involved in the chemoresistance of small cell lung cancer (SCLC) and to correlate the drug resistance associated proteins such as bcl-2, bcl-X(L) and p53. Drug-resistant small lung cancer cells (H69AR) which were originally developed by ADM and which demonstrated multi-drug resistance to chemotherapeutic agents were used in the study. Western blot analysis revealed that H69AR cells over-expressed the proteins Etk and bcl-X(L), but not bcl-2 and p53 when compared to parent H69 cells. Knockdown of Etk expression by Etk-specific small interfering RNA sensitised H69AR cells to chemotherapeutic drugs and inhibited bcl-X(L) expression but not bcl-2 and p53. Co-immunoprecipitation was performed to further evaluate the relationship between Etk and bcl-X(L) with anti-Etk and anti-phospho-Etk antibodies. The bcl-X(L) was accompanied with a robust increase of Etk and tyrosine phosphorylated Etk at Tyr-40 in H69AR cells. In conclusion, our results suggest that non-receptor tyrosine kinase Etk is involved in drug resistance to SCLC by mediating bcl-X(L) via Tyr(P)-40. The potential approach for downregulation of Etk activity on expression would be a novel, potentially clinically practical strategy for interfering with chemoresistance in SCLC.
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PMID:Non-receptor tyrosine kinase Etk regulation of drug resistance in small-cell lung cancer. 2000 64

The vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2), also called fetal liver kinase 1 (FLK1) in mice and kinase insert domain receptor (KDR) in humans, is an endothelial cell specific receptor tyrosine kinase that mediates lung cancer angiogenesis. We hypothesized that an active immunotherapy approach targeting FLK1 may inhibit lung cancer growth and metastasis. To test this hypothesis, we evaluated whether immune responses to FLK1 could be elicited in mice by immunization with an orally administered DNA vaccine encoding the extracellular domain (ECD) of FLK1 (pcDNA3.1-FLK1(ECD)) carried by attenuated Salmonella typhimurium. We found that the vaccine was effective at protective antitumor immunity in Lewis lung carcinoma models in mice by breaking immune tolerance to FLK1 self-antigen. Both FLK1-specific humoral and cellular immune responses against endothelial cells can be induced in mice by immunization with pcDNA3.1-FLK1(ECD). Immunization with pcDNA3.1-FLK1(ECD) resulted in tumor suppression and prolonged survival in mice challenged with Lewis lung carcinomas cells. Experimental pulmonary metastases were strongly inhibited in pcDNA3.1-FLK1(ECD) immunized mice challenged with Lewis lung carcinoma cells. Thus, we conclude that the plasmid DNA vaccine encoding the extracellular domain of FLK1 could be an important component of FLK1 DNA vaccine to prevent lung carcinoma recurrence and metastasis after surgery.
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PMID:Orally administered DNA vaccine delivery by attenuated Salmonella typhimurium targeting fetal liver kinase 1 inhibits murine Lewis lung carcinoma growth and metastasis. 2011 36

The mutant receptor tyrosine kinase EGFR is a validated and therapeutically amenable target for genotypically selected lung cancer patients. Here we present the synthesis and biological evaluation of a series of 6- and 7-substituted 4-anilinoquinolines as potent type I inhibitors of clinically relevant mutant variants of EGFR. Quinolines 3a and 3e were found to be highly active kinase inhibitors in biochemical assays and were further investigated for their biological effect on EGFR-dependent Ba/F3 cells and non-small cell lung cancer (NSCLC) cell lines.
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PMID:Synthesis and biological evaluation of 4-anilinoquinolines as potent inhibitors of epidermal growth factor receptor. 2022 33

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, are the first targeted therapy drugs approved for the treatment of advanced non-small-cell lung cancer (NSCLC). Interestingly, treatment with these small molecule, reversible EGFR-TKIs leads to more positive response rates in patients with adenocarcinoma, in females, Asians, and patients with no history of smoking. Positive responses to treatment in these populations may be due to the increased prevalence of mutations in the EGFR gene. Several distinct mutations in the EGFR gene have been identified in specimens from patients with NSCLC who responded to treatment with anilinoquinazoline EGFR inhibitors. However, despite the dramatic initial response to TKIs, most lung cancer patients relapse and subsequently become resistant to the drug, a process termed acquired resistance. The precise mechanisms underlying acquired resistance remain unclear. Resistance to EGFR-TKIs could result from several potential mechanisms, including development of a secondary mutation in EGFR (such as T790M), amplification of the MET receptor tyrosine kinase gene, or overexpression of other receptor tyrosine kinases.
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PMID:Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib. 2040 20

Sprouty proteins are potent receptor tyrosine kinase inhibitors that antagonize growth factor signaling and are involved in lung development. However, little is known about the regulation or targets of Sprouty-4 (Spry4) in lung cancer. Our study aimed to determine the role of Spry4 in non-small cell lung cancer (NSCLC). We found that Spry4 mRNA expression was decreased in NSCLC cell lines and in dysplastic lung cell lines compared with a nontransformed cell line, suggesting that Spry4 has tumor-suppressing activity. When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. Changes in epithelial and mesenchymal markers indicated that Spry4 expression induces a reversal of the epithelial to mesenchymal transition characteristic of tumor cells. Treatment of a nontransformed lung epithelial cell line with short hairpin RNA to Spry4 led to the decreased expression of epithelial markers and increased cell growth, supporting the concept of Spry4 acting as a tumor suppressor. We showed that the activity of the Spry4 promoter is increased by Wnt7A/Fzd9 signaling through peroxisome proliferator-activated receptor gamma. These data present previously undescribed targets of Spry4 and suggest that Spry4 is a downstream target of Wnt7A/Fzd 9 signaling. Spry4 may have efficacy in the treatment of NSCLC.
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PMID:Sprouty-4 inhibits transformed cell growth, migration and invasion, and epithelial-mesenchymal transition, and is regulated by Wnt7A through PPARgamma in non-small cell lung cancer. 2050 43

Platelet-derived growth factor (PDGF) is a significant mediator in the proliferation of cancer-associated stromal fibroblasts (CAFs). The inhibition of CAF proliferation by blocking PDGF signaling could lead to a development of novel cancer therapy. We analyzed whether inhibiting proliferation of lung CAFs by imatinib mesylate, which has inhibitory activity on PDGF-receptor tyrosine kinase, could suppress the proliferative activity of lung cancer cells which coexisted in the tumor tissue. First, we established primary cultured fibroblasts from human lung cancer tissues. RT-PCR analysis showed that PDGF-receptors (PDGFRalpha and beta) were more highly expressed in the fibroblasts, whereas PDGFs (PDGF-A, and -B) were more in lung cancer cell lines. Western blotting showed that imatinib treatment inhibited phosphorylation of PDGFRbeta, Akt, and Erk1/2 in the fibroblasts. The treatment also significantly inhibited the proliferative activity of the fibroblasts. The inhibitory effects were exerted more definitely in co-administering imatinib and PDGF-BB, a dimer of the polypeptide chains of B, than in administering imatinib alone. The conditioned media of the fibroblasts significantly increased the proliferative activity of human lung cancer cell line A549 compared to control culture medium. The proliferation-stimulating effect on A549 cells decreased significantly in the conditioned media of the primary cultured fibroblasts that had been treated with imatinib. Our results suggest that imatinib has antitumor activity which is exerted by reducing the proliferation-stimulating effect of CAFs on lung cancer cells, as well as inhibiting the proliferation of CAFs, by way of blocking PDGF signaling.
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PMID:Imatinib mesylate inhibits the proliferation-stimulating effect of human lung cancer-associated stromal fibroblasts on lung cancer cells. 2081 9

Angiogenesis is essential for cancer growth and progression. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis. The addition of bevacizumab, an antibody to vascular endothelial growth factor (VEGF), to paclitaxel and carboplatin improves survival compared with chemotherapy alone in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are a new class of drugs that target the TK domain of the VEGF receptors. To evaluate the role of this class of agents in the treatment of NSCLC, some phase II and phase III studies using these agents alone or in combination with other agents have been completed. This review summarizes the currently available data on VEGFR TKIs in the treatment of NSCLC.
Clin Lung Cancer 2010 Sep 01
PMID:Vascular endothelial growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. 2083 56

The Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase first identified as the product of a gene rearrangement in Anaplastic Large Cell Lymphoma. ALK has subsequently been found to be rearranged, mutated, or amplified in a further series of tumours including neuroblastoma, and Non-Small Cell Lung Cancer. There is strong preclinical evidence that ALK is a driving force for oncogenesis in these cases, and that inhibition of ALK kinase activity results in anti-tumoural efficacy. These observations have sparked the development of small molecule kinase inhibitors, the most advanced of which is currently in clinical testing and which has shown promising preliminary activity in the subset of lung cancer patients whose tumours harbour activated ALK. In this review, we describe the various oncogenic forms of ALK, relevant clinical settings, and give a detailed overview of current drug discovery efforts in the field.
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PMID:Anaplastic Lymphoma Kinase: role in specific tumours, and development of small molecule inhibitors for cancer therapy. 2093 3

Protein tyrosine kinase-7 (PTK7) is a catalytically inactive receptor tyrosine kinase (RTK). PTK7 is upregulated in many common human cancers, including colon cancer, lung cancer, gastric cancer and acute myeloid leukemia. The reason for this up-regulation is not yet known. To explore the functional role of PTK7, the expression of PTK7 in HCT 116 cells was examined using small interference (siRNA)-mediated gene silencing. Following transfection, the siRNA successfully suppressed PTK7 mRNA and protein expression. Knocking down of PTK7 in HCT 116 cells inhibited cell proliferation compared to control groups and induced apoptosis. Furthermore, this apoptosis was characterized by decreased mitochondrial membrane potential and activation of caspase-9 and -10. Addition of a caspase-10 inhibitor totally blocked this apoptosis, suggesting that caspase-10 may play a critical role in PTK7-knockdown-induced apoptosis, downstream of mitochondria. These observations may indicate a role for PTK7 in cell proliferation and cell apoptosis and may provide a potential therapeutic pathway for the treatment of a variety of cancers.
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PMID:Silencing of PTK7 in colon cancer cells: caspase-10-dependent apoptosis via mitochondrial pathway. 2110 79

Vandetanib is a multi-targeted receptor tyrosine kinase inhibitor that is in clinical development for the treatment of solid tumours. This preclinical study examined the inhibition of two key signalling pathways (VEGFR-2, EGFR) at drug concentrations similar to those achieved in the clinic, and their contribution to direct and indirect antitumour effects of vandetanib. For in vitro studies, receptor phosphorylation was assessed by Western blotting and ELISA, cell proliferation was assessed using a cell viability endpoint, and effects on cell cycle determined using flow cytometry. For in vivo studies, Western blotting, ELISA and immunohistochemistry (IHC) were used to assess receptor phosphorylation. Cell culture experiments demonstrated that anti-proliferative effects of vandetanib resulted from inhibition of either EGFR or VEGFR-2 signalling in endothelial cells, but were associated with inhibition of EGFR signalling in tumour cells. Vandetanib inhibited both EGFR and VEGFR-2 signalling in normal lung tissue and in tumour xenografts. In a lung cancer model expressing an activating EGFR mutation, the activity of vandetanib was similar to that of a highly selective EGFR inhibitor (gefitinib), and markedly greater than that of a highly selective VEGFR inhibitor (vatalanib). These data suggest that at the plasma exposures achieved in the clinic, vandetanib will significantly inhibit both VEGFR-2 and EGFR signalling, and that both inhibition of angiogenesis and direct inhibition of tumour cell growth can contribute to treatment response.
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PMID:Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer. 2153 41


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