Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erlotinib is a small molecule tyrosine kinase inhibitor that is used as an anticancer agent. Most patients develop a pustular facial dermatitis within the first week of treatment. Pyogenic granulomas of the nail folds are another typical adverse event occurring in about 10-15% of cases. We report on a patient who developed a generalized dermatitis characterized by neutrophilic spongiosis. Neutrophilic inflammation has been observed in several drugs that interfere with EGFR signaling, suggesting a class effect. The present case may be yet another manifestation of this particular reaction pattern.
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PMID:Generalized xerotic dermatitis with neutrophilic spongiosis induced by erlotinib (Tarceva). 1818 20

Erlotinib (Tarceva) is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor initially approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of at least one prior chemotherapy regimen. In this report, we present the pivotal study that led to the approval of erlotinib in combination with gemcitabine (Gemzar) in patients with locally advanced/metastatic chemonaive pancreatic cancer patients. The combination demonstrated a statistically significant increase in overall survival accompanied by an increase in toxicity. Physicians and patients now have a new option for the treatment of locally advanced/metastatic adenocarcinoma of the pancreas.
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PMID:Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas. 1824 17

New targeted treatments offer an important opening towards the improvement of the results in the treatment of lung cancer. Currently two types of therapeutic targets are developed successfully in the treatment of advanced non-small cell lung cancer: tumour angiogenesis and growth factor receptors. Therapeutic drugs are small molecules inhibitors and the monoclonal antibodies. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor receptor, VEGF, an important molecule in tumour angiogenesis. The combination of bevacizumab with first line chemotherapy increases the median survival of advanced NSCLC with a few weeks. At this moment no biomarker predicting efficacy that can help in the selection of patients is unfortunately available for this expensive treatment, although it is important to select patients based on specific contra-indications. The epidermal growth factor receptor (EGFR or HER1) is activated in NSCLC by several mechanisms. The small molecules erlotinib and gefitinib are targeting the intracellular kinase domain of the EGF receptor, thus inhibiting the signal transduction cascade. Erlotinib is currently registered and reimbursed in Belgium. The concomitant use of these small molecules with chemotherapy is ineffective in non-selected NSCLC patients. On the other hand, these molecules have great activity in patients with tumours having a constitutionally activated EGFR. Changes in the kinase domain of the receptor give rise to extremely high response rates and unexpectedly improved survival duration in patients with NSCLC. Currently studies are exploring whether erlotinib should be employed in the first line treatment of NSCLC. The FIELT study is a translational academic and multicentre phase II study in Belgium and Luxemburg addressing this issue. Specific mechanisms of resistance for these agents are gradually discovered and the new drugs being able to overcome these resistances are at the horizon.
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PMID:[Targeted therapies in the treatment of non-small cell lung cancer]. 1839 Apr 17

The Epidermal Growth Factor Receptor (EGFR) family, including EGFR, HER2, HER3, and HER4, is implicated in the development and progression of cancer, and is expressed in many human epithelial malignancies, including Non-Small Cell Lung Cancer (NSCLC). Several molecules were synthesized to inhibit the extracellular domain of EGFR, such as cetuximab (Erbitux), the extracellular domain of HER2, such as trastuzumab (Herceptin) or the EGFR tyrosine kinase domain, such as gefitinib (Iressa) and erlotinib (Tarceva). Gefitinib and erlotinib are orally active, selective EGFR tyrosine-kinase inhibitors (EGFR-TKI) that produce objective response rates in about 10% of advanced NSCLC. More recently, erlotinib produced a significant improvement in survival when compared to placebo in pretreated NSCLCs. Among clinical characteristics, although female gender, and adenocarcinoma histology, showed to be significantly associated to TKI sensitivity, never smoking history is probably the most relevant factor. Presence of specific EGFR gene mutations or EGFR gene amplification confer a particularly sensitive phenotype, and patients with activation of the anti-apoptotic protein Akt are more sensitive, when Akt activation is sustained by a EGFR dependent mechanism. Cetuximab is a human-murine chimeric anti-EGFR IgG monoclonal antibody that has demonstrated both in vitro and in vivo antitumor activity in tumor cell lines expressing EGFR. It has shown impressive activity when combined with radiation by increasing the antitumor effect of radiation therapy. Cetuximab has a synergistic effect with cisplatin and may play a role in reversing resistance to chemotherapy. Cetuximab demonstrated to be active in pretreated NSCLCs, and its activity as first-line therapy in combination with chemotherapy is currently under evaluation. Efforts should be made for the identification of biological mechanism underlying cetuximab sensitivity and emerging data suggest that the drugs is more active in patients with EGFR gene amplification. In NSCLC, trastuzumab produced disappointing results when combined with chemotherapy, but probably patients were not properly selected. Recent findings in gefitinib treated patients support HER2 analysis by fluorescence in situ hybridization as a complementary test for selection of patient candidate for EGFR targeted therapies. Combination of EGFR targeting agents with other biological drugs is under investigation.
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PMID:Epidermal growth factor receptor (EGFR) targeted therapies in non-small cell lung cancer (NSCLC). 1839 76

Human cancer cell lines that can be propagated and manipulated in culture have proven to be excellent models for studying many aspects of gene function in cancer. In addition, they can provide a powerful system for assessing the molecular determinants of sensitivity to anticancer drugs. They have also been used in recent studies to identify genomic alterations and gene expression patterns that provide important insights into the genetic features that distinguish the properties of tumor cells associated with similar histologies. We have established a large repository of human tumor cell lines (>1000) corresponding to a wide variety of tumor types, and we have developed a methodology for profiling the collection for sensitivity to putative anticancer compounds. The rationale for examining tumor cell lines on this relatively large scale reflects accumulating evidence indicating that there is substantial genetic heterogeneity among human tumor cells-even those derived from tumors of similar histologies. Thus, to develop an accurate picture of the molecular determinants of tumorigenesis and response to therapy, it is essential to study the nature of such heterogeneity in a relatively large sample set. Here, we describe the methodologies used to conduct such screens and we describe a "proof-of-concept" screen using the EGFR kinase inhibitor, erlotinib (Tarceva), with a panel of lung cancer lines to demonstrate a correlation between EGFR mutations and drug sensitivity.
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PMID:High-throughput lung cancer cell line screening for genotype-correlated sensitivity to an EGFR kinase inhibitor. 1841 59

This study identifies a novel cross-talk paradigm between the type I insulin-like growth factor receptor (IGF1R) and epidermal growth factor receptor (EGFR) in colon cancer cells. IGF1R activation by ligand exposure in growth factor-deprived cells induces Akt activation in the FET, CBS, and GEO colon cancer cell lines. Investigation of IGF1R-mediated signaling pathways using small interfering RNA approaches indicated that, as expected, phosphatidylinositol 3'-kinase (PI3K) was activated by IGF1R. Mitogen-activated protein kinase (MAPK) activity as reflected by phospho-extracellular signal-regulated kinase (ERK) induction was not significantly activated until later times following release of these cells from growth factor deprivation stress. The appearance of phospho-ERK was proximal to EGFR activation. Treatment of cells with the PI3K inhibitor LY294002 before release from stress resulted in a concentration-dependent loss of EGFR activation, whereas treatment with the MAPK inhibitor PD98059 did not block EGFR activation, indicating that EGFR activation was downstream of the IGF1R/PI3K pathway. PD98059 inhibition of MAPK was associated with a concentration-dependent reduction in EGFR-mediated phospho-ERK. EGFR inhibitor blocked induction of phospho-ERK, showing that MAPK activity was a consequence of EGFR-mediated signaling. On the other hand, a small-molecule IGF1R inhibitor, PQIP, blocked Akt phosphorylation. The divergent signaling functions of IGF1R and EGFR suggested the potential for synergism by a combination of therapy directed at the two receptors. Combination treatment with PQIP and EGFR inhibitor Tarceva resulted in synergistic effects as indicated by combination index analysis in all three cell lines tested.
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PMID:Heterogeneity of receptor function in colon carcinoma cells determined by cross-talk between type I insulin-like growth factor receptor and epidermal growth factor receptor. 1882 58

ErbBs signalling is always associated with the development of the majority of solid cancers via both the MAPK pathway leading to cell cycle progression and the PI3K pathway causing cell survival. As a consequence, many ErbB antagonists have been developed and patented for cancer treatment purposes. These antagonists belong to two drug classes: monoclonal antibodies (mAbs) and small molecules competing with ATP and inhibiting the tyrosine kinase domain (TKIs). Three patented mAbs are currently approved in clinical cancer treatment: Trastuzumab (Herceptin) directed against HER2 and used to treat breast cancer, Cetuximab and Panitumumab which are anti-EGFR antibodies approved for colorectal cancer treatment. Unfortunately, these mAbs are facing cancer resistance mediated by paracrine activation of other ErbB members or compensatory ErbB signalling factors. In parallel, three TKIs have been approved to treat cancer: Gefitinib (Iressa), Erlotinib (Tarceva) inhibiting specifically EGFR and approved to treat non small cell lung cancer and Lapatinib (Tykerb) which has the dual specificity EGFR/HER2 and recently approved to treat metastatic breast cancer. These TKIs are also facing resistance mutations within the TK domain which increase its affinity to ATP. Resistance problems are leading to the adoption of a new strategy based on the combination of different therapies and this is likely to be the most promising future of cancer treatments.
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PMID:ErbB antagonists patenting: "playing chess with cancer". 1907 65

HeadHER1/EGFR is known to play a pivotal role in tumorigenesis and is overexpressed in up to 80% of NSCLCs. The study of an Expanded Access Clinical Program of Erlotinib in NSCLC is a phase IV open-label, non-randomized, multicenter trial in patients with advanced (inoperable stage IIIb/IV) NSCLC who were eligible for treatment with erlotinib but had no access to trial participation. Patients for the study from Bosnia and Herzegovina (B&H) were selected from two Clinical centres (Sarajevo and Banja Luka). The aim of study was to evaluated efficacy and tolerability of erlotinib monotherapy in this setting. All patients who received at least one dose of erlotinib and data were entered in the database as of the CRF cut-off date of 14th May 2008 were included in analysis of data (n = 19). This population is defined as the Intent to Treat (ITT) population and includes all patients who had at least one dose of erlotinib regardless of whether major protocol violations were incurred. The findings are consistent with the results of the randomized, placebo-controlled BR.21 study. Indicating that erlotinib is an effective option for patients with advanced NSCLC who are unsuitable for, or who have previously failed standard chemotherapy. In B&H group of patients DCR was almost 84%, and PFS was approximately 24,7 weeks (compared with 44% and 9,7 weeks for erlotinib reported in phase III). Almost three quarter of the patients received erlotinib as their second line of therapy. Overall, erlotinib was well tolerated; there were no patients who withdrew due to a treatment-related AE (mainly rash) and there were few dose reductions. 24% of patients experienced an SAE (most commonly gastrointestinal (GI) disorders).
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PMID:Our experiences with erlotinib in second and third line treatment patients with advanced stage IIIB/ IV non-small cell lung cancer. 1912 14

Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment.
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PMID:Tyrosine kinase blockers: new hope for successful cancer therapy. 1914 83

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib improves survival of lung cancer as second- or third-line therapy. However, after an initial response, most patients will recur, particularly within the central nervous system. The present study reports the case of a 27-yr-old nonsmoking male presenting with a metastatic lung adenocarcinoma with EGFR exon 19 deletion, associated with sensitivity to EGFR-TKI. Gefitinib, followed by chemotherapy and finally erlotinib resulted in prolonged disease control, until multiple liver metastases were detected. After stopping EGFR-TKI, brain metastases with carcinomatous meningitis were diagnosed. A secondary T790M mutation, associated with resistance to EGFR-TKI, was found on the liver biopsy but not in the cerebrospinal fluid. Erlotinib was reintroduced and allowed a quick neurological improvement, even though the extra-cranial disease remained resistant to erlotinib. The present report underscores the interest of molecular monitoring in lung cancer. Persistent cerebral tyrosine kinase inhibitor sensitivity should be considered in patients presenting with an early central nervous system relapse after stopping epidermal growth factor receptor tyrosine kinase inhibitor, even with a T790M-resistant mutation in noncerebral metastases. Questions remain concerning the selection of sub-clones during epidermal growth factor receptor tyrosine kinase inhibitor therapy, which could differ according to metastatic sites, especially in the central nervous system.
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PMID:EGFR-TKI and lung adenocarcinoma with CNS relapse: interest of molecular follow-up. 1918 17


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