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Dominant-negative Notch3 receptor inhibits mitogen-activated protein kinase pathway and the growth of human lung cancers.
Haruki N, Kawaguchi KS, Eichenberger S, Massion PP, Olson S, Gonzalez A, Carbone DP, Dang TP
(2005) Cancer Res 65: 3555-61
MeSH Terms: Apoptosis, Cell Cycle Proteins, Cell Growth Processes, Cell Line, Tumor, Down-Regulation, Dual Specificity Phosphatase 1, Enzyme Inhibitors, ErbB Receptors, Humans, Immediate-Early Proteins, Lung Neoplasms, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 1, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins, Quinazolines, Receptor, Notch3, Receptors, Cell Surface, Receptors, Notch, Transfection, Tyrphostins
Show Abstract · Added March 5, 2014
Notch3 is a member of an evolutionarily conserved family of cell surface receptors important in cell-fate determination in both vertebrates and invertebrates. Significant data support the role of Notch pathway in cancer development, although the conflicting role of Notch signaling pathways in tumorigenesis suggests that its action is highly context-dependent. Furthermore, although Notch receptors signal primarily through the regulation of hairy enhancer of split (HES) and HES-related (HRT) genes, they are known to crosstalk with other signaling pathways, including the epidermal growth factor (EGF) and the mitogen-activated protein kinase pathways. Whereas much is known about the role of Notch1 in human cancer, the role of Notch3 in epithelial tumors, such as lung carcinomas, has not been well established. In this study, we show that Notch3 is expressed in 80 of 207 (39%) resected human lung tumors and that its expression is positively correlated with EGF receptor expression. Inhibition of the Notch3 pathway using a dominant-negative receptor dramatically reduces growth in soft agar and increases growth factor dependence. We also find that Notch inhibition increases sensitivity to EGF receptor tyrosine kinase inhibition and decrease in phosphorylation of the mitogen-activated protein kinase. These observations support a role for Notch3 signaling in lung cancer, and one potential mechanism of maintaining the neoplastic phenotype is through the modulation of the EGF pathway.
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24 MeSH Terms
Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions.
Pao W, Miller VA
(2005) J Clin Oncol 23: 2556-68
MeSH Terms: Carcinoma, Non-Small-Cell Lung, Clinical Trials as Topic, DNA Mutational Analysis, ErbB Receptors, Erlotinib Hydrochloride, Gefitinib, Gene Amplification, Humans, Lung Neoplasms, Mutation, Protein Kinase Inhibitors, Quinazolines, Treatment Outcome
Show Abstract · Added March 24, 2014
PURPOSE - Gefitinib and erlotinib are small molecules that selectively inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity. When these drugs were introduced into the clinic, the specific targets affected in human tumors were unknown. In April 2004, two groups reported that mutations in the tyrosine kinase domain of EGFR are strongly associated with gefitinib sensitivity in patients with non-small-cell lung cancer (NSCLC). We subsequently extended these findings and showed that such mutations are also associated with sensitivity to erlotinib. Here, we present current knowledge about EGFR mutations in the context of clinical trials involving gefitinib and erlotinib in NSCLC.
DESIGN - This article reviews the rationale for targeting EGFR, the development of gefitinib and erlotinib, the discovery of EGFR mutations, and subsequent studies to define the incidence, spectrum, and functions of EGFR mutations.
RESULTS - The discovery of EGFR mutations promises to alter the ways in which we consider and treat NSCLC.
CONCLUSION - This information can guide practitioners and help them inform their patients about EGFR mutations and their impact on the treatment of NSCLC.
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13 MeSH Terms
Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.
Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H
(2005) PLoS Med 2: e73
MeSH Terms: Adenocarcinoma, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, DNA Mutational Analysis, Disease Progression, Drug Resistance, Neoplasm, ErbB Receptors, Erlotinib Hydrochloride, Exons, Female, Gefitinib, Humans, Lung Neoplasms, Middle Aged, Point Mutation, Quinazolines, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured
Show Abstract · Added March 24, 2014
BACKGROUND - Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor receptor (EGFR). Despite initial responses, patients eventually progress by unknown mechanisms of "acquired" resistance.
METHODS AND FINDINGS - We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. Tumor cells from a sixth patient with a drug-sensitive EGFR mutation whose tumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation. This mutation was not detected in untreated tumor samples. Moreover, no tumors with acquired resistance had KRAS mutations, which have been associated with primary resistance to these drugs. Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib. Interestingly, a mutation analogous to T790M has been observed in other kinases with acquired resistance to another kinase inhibitor, imatinib (Gleevec).
CONCLUSION - In patients with tumors bearing gefitinib- or erlotinib-sensitive EGFR mutations, resistant subclones containing an additional EGFR mutation emerge in the presence of drug. This observation should help guide the search for more effective therapy against a specific subset of lung cancers.
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18 MeSH Terms
The epidermal growth factor receptor as a target for colorectal cancer therapy.
Lockhart AC, Lockhart C, Berlin JD
(2005) Semin Oncol 32: 52-60
MeSH Terms: Aminoquinolines, Aniline Compounds, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Cell Transformation, Neoplastic, Cetuximab, Colorectal Neoplasms, Disease Progression, ErbB Receptors, Erlotinib Hydrochloride, Gefitinib, Humans, Lapatinib, Organic Chemicals, Panitumumab, Prognosis, Pyrimidines, Pyrroles, Quinazolines, Signal Transduction
Show Abstract · Added March 20, 2014
The epidermal growth factor receptor (EGFR) is the prototypical member of the erbB receptor family. The EGFR axis is activated by a variety of ligands that are crucial in the formation and propagation of many tumors, including colorectal cancer, through their effects on cell signaling pathways, cellular proliferation, control of apoptosis, and angiogenesis. The importance of the EGFR axis in tumorigenesis and tumor progression makes it an attractive target for the development of anticancer therapies. A variety of targeting strategies to exploit the role of EGFR in tumors have been employed. The most highly developed of these anti-EGFR approaches are the monoclonal antibodies and the tyrosine kinase inhibitors (TKIs). Clinical evaluations of these compounds have yielded some promising results. The role of the EGFR axis in colorectal cancer formation and progression is reviewed and the clinical development of these anticancer EGFR-targeted drugs is reviewed and updated.
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21 MeSH Terms
KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.
Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, Zakowski MF, Heelan RT, Kris MG, Varmus HE
(2005) PLoS Med 2: e17
MeSH Terms: Adenocarcinoma, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Decision Making, Drug Resistance, Neoplasm, Erlotinib Hydrochloride, Gefitinib, Genes, ras, Humans, Lung Neoplasms, Quinazolines, Treatment Outcome
Show Abstract · Added March 24, 2014
BACKGROUND - Somatic mutations in the gene for the epidermal growth factor receptor (EGFR) are found in adenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, KRAS, and mutations in EGFR and KRAS appear to be mutually exclusive.
METHODS AND FINDINGS - We sought to determine whether mutations in KRAS could be used to further enhance prediction of response to gefitinib or erlotinib. We screened 60 lung adenocarcinomas defined as sensitive or refractory to gefitinib or erlotinib for mutations in EGFR and KRAS. We show that mutations in KRAS are associated with a lack of sensitivity to either drug.
CONCLUSION - Our results suggest that treatment decisions regarding use of these kinase inhibitors might be improved by determining the mutational status of both EGFR and KRAS.
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12 MeSH Terms
Early changes in protein expression detected by mass spectrometry predict tumor response to molecular therapeutics.
Reyzer ML, Caldwell RL, Dugger TC, Forbes JT, Ritter CA, Guix M, Arteaga CL, Caprioli RM
(2004) Cancer Res 64: 9093-100
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Biomarkers, Tumor, Drug Synergism, ErbB Receptors, Erlotinib Hydrochloride, Female, Humans, Mammary Neoplasms, Experimental, Mice, Mice, Transgenic, Molecular Sequence Data, Predictive Value of Tests, Protein Kinase Inhibitors, Proteome, Quinazolines, Receptor, ErbB-2, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Trastuzumab
Show Abstract · Added March 5, 2014
Biomarkers that predict therapeutic response are essential for the development of anticancer therapies. We have used matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to directly analyze protein profiles in mouse mammary tumor virus/HER2 transgenic mouse frozen tumor sections after treatment with the erbB receptor inhibitors OSI-774 and Herceptin. Inhibition of tumor cell proliferation and induction of apoptosis and tumor reduction were predicted by a >80% reduction in thymosin beta4 and ubiquitin levels that were detectable after 16 hours of a single drug dose before any evidence of in situ cellular activity. These effects were time- and dose-dependent, and their spatial distribution in the tumor correlated with that of the small-molecule inhibitor OSI-774. In addition, they predicted for therapeutic synergy of OSI-774 and Herceptin as well as for drug resistance. These results suggest that drug-induced early proteomic changes as measured by MALDI-MS can be used to predict the therapeutic response to established and novel therapies.
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21 MeSH Terms
Mechanisms of resistance development against trastuzumab (Herceptin) in an in vivo breast cancer model.
Ritter CA, Bianco R, Dugger T, Forbes J, Qu S, Rinehart C, King W, Arteaga CL
(2004) Int J Clin Pharmacol Ther 42: 642-3
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Drug Resistance, Neoplasm, Erlotinib Hydrochloride, Female, Mice, Mice, Inbred BALB C, Protein Kinase Inhibitors, Quinazolines, Rats, Receptor, ErbB-2, Trastuzumab
Added March 5, 2014
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14 MeSH Terms
Practical management of patients with non-small-cell lung cancer treated with gefitinib.
Shah NT, Kris MG, Pao W, Tyson LB, Pizzo BM, Heinemann MH, Ben-Porat L, Sachs DL, Heelan RT, Miller VA
(2005) J Clin Oncol 23: 165-74
MeSH Terms: Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Diarrhea, Drug Interactions, ErbB Receptors, Exanthema, Eye, Female, Gefitinib, Humans, Lung Diseases, Interstitial, Lung Neoplasms, Male, Patient Education as Topic, Quinazolines, Radiography
Show Abstract · Added March 24, 2014
PURPOSE - The use of gefitinib, the first drug approved to inhibit the epidermal growth factor receptor tyrosine kinase, is indicated in patients with non-small-cell lung cancer with tumors progressive after chemotherapy. The unique mechanism of action of this agent leads to distinctive patterns of response and toxicity in persons with lung cancer. Many of the principles of management relevant to gefitinib are distinct from those with conventional cytotoxic drugs. To meet this need, we present practical guidelines on the use of gefitinib in patients with non-small-cell lung cancer.
METHODS - This article reviews gefitinib's indications, dosing, response phenomena, and patterns of relapse in individuals with radiographic response.
RESULTS - We present our recommendations for the management of rash and diarrhea caused by this agent.
CONCLUSION - This information can guide practitioners and help them inform their patients about what to expect when they receive gefitinib.
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16 MeSH Terms
EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.
Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H
(2004) Proc Natl Acad Sci U S A 101: 13306-11
MeSH Terms: Adenocarcinoma, Amino Acid Sequence, Base Sequence, Carcinoma, Non-Small-Cell Lung, ErbB Receptors, Erlotinib Hydrochloride, Female, Gefitinib, Humans, Lung Neoplasms, Male, Molecular Sequence Data, Mutation, Quinazolines
Show Abstract · Added March 24, 2014
Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.
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14 MeSH Terms
Predicting sensitivity of non-small-cell lung cancer to gefitinib: is there a role for P-Akt?
Pao W, Miller VA, Venkatraman E, Kris MG
(2004) J Natl Cancer Inst 96: 1117-9
MeSH Terms: Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Enzyme Inhibitors, ErbB Receptors, Gefitinib, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Mitogen-Activated Protein Kinase Kinases, Predictive Value of Tests, Prognosis, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Quinazolines, Treatment Outcome
Added March 24, 2014
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17 MeSH Terms