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           Search results for: BIBW-2992 (Afatinib) Mechanisms: EGFR HER inhibitor   

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#28961841   2017/09/29 Save this To Up

Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC).

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance.

2388 related Products with: Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC).

Non small cell lung carci Lung non small cell cance High density non small ce Middle advanced stage lun Multiple lung carcinoma ( Non-small cell lung cance Non small cell lung carci Non small cell lung carci Mid advanced stage bladde Middle advanced stage bre Middle advanced stage bre Mid advanced stage uterin

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#28730963   2017/07/21 Save this To Up

Increased expression of IRE1α associates with the resistant mechanism of osimertinib (AZD9291)-resistant non-small cell lung cancer HCC827/OSIR cells.

Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients.

2575 related Products with: Increased expression of IRE1α associates with the resistant mechanism of osimertinib (AZD9291)-resistant non-small cell lung cancer HCC827/OSIR cells.

Lung non small cell cance Non-small cell lung cance Non small cell lung carci Non small cell lung carci Non small cell lung carci Lung small cell carcinoma Human Small Intestine Mic Dog Receptor-binding canc Mouse Anti-Human CD34 Tar Small cell lung carcinoma Non small cell lung carci Non small cell lung carci

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#28656962   2017/06/28 Save this To Up

Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein.

Germline mutations in the Folliculin (FLCN) tumour suppressor gene result in fibrofolliculomas, lung cysts and renal cancers, but the precise mechanisms of tumour suppression by FLCN remain elusive. Here we identify Rab7A, a small GTPase important for endocytic trafficking, as a novel FLCN interacting protein and demonstrate that FLCN acts as a Rab7A GTPase-activating protein. FLCN(-/-) cells display slower trafficking of epidermal growth factor receptors (EGFR) from early to late endosomes and enhanced activation of EGFR signalling upon ligand stimulation. Reintroduction of wild-type FLCN, but not tumour-associated FLCN mutants, suppresses EGFR signalling in a Rab7A-dependent manner. EGFR signalling is elevated in FLCN(-/-) tumours and the EGFR inhibitor afatinib suppresses the growth of human FLCN(-/-) cells as tumour xenografts. The functional interaction between FLCN and Rab7A appears conserved across species. Our work highlights a mechanism explaining, at least in part, the tumour suppressor function of FLCN.

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#28500237   2017/05/13 Save this To Up

Resistance to RET-Inhibition in RET-Rearranged NSCLC Is Mediated By Reactivation of RAS/MAPK Signaling.

Oncogenic rearrangements in RET are present in 1%-2% of lung adenocarcinoma patients. Ponatinib is a multi-kinase inhibitor with low-nanomolar potency against the RET kinase domain. Here, we demonstrate that ponatinib exhibits potent antiproliferative activity in RET fusion-positive LC-2/ad lung adenocarcinoma cells and inhibits phosphorylation of the RET fusion protein and signaling through ERK1/2 and AKT. Using distinct dose escalation strategies, two ponatinib-resistant LC-2/ad cell lines, PR1 and PR2, were derived. PR1 and PR2 cell lines retained expression, but not phosphorylation of the RET fusion and lacked evidence of a resistance mutation in the RET kinase domain. Both resistant lines retained activation of the MAPK pathway. Next-generation RNA sequencing revealed an oncogenic NRAS p.Q61K mutation in the PR1 cell. PR1 cell proliferation was preferentially sensitive to siRNA knockdown of NRAS compared with knockdown of RET, more sensitive to MEK inhibition than the parental line, and NRAS dependence was maintained in the absence of chronic RET inhibition. Expression of NRAS p.Q61K in RET fusion expressing TPC1 cells conferred resistance to ponatinib. PR2 cells exhibited increased expression of EGFR and AXL. EGFR inhibition decreased cell proliferation and phosphorylation of ERK1/2 and AKT in PR2 cells, but not LC-2/ad cells. Although AXL inhibition enhanced PR2 sensitivity to afatinib, it was unable to decrease cell proliferation by itself. Thus, EGFR and AXL cooperatively rescued signaling from RET inhibition in the PR2 cells. Collectively, these findings demonstrate that resistance to ponatinib in RET-rearranged lung adenocarcinoma is mediated by bypass signaling mechanisms that result in restored RAS/MAPK activation. Mol Cancer Ther; 16(8); 1623-33. ©2017 AACR.

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#28416737   2017/04/18 Save this To Up

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR.

The aim of this work was to investigate the efficacy of sequential treatment with first-, second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the mechanisms of acquired resistance occurring during the sequential use of these inhibitors.

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BIBW-2992 (Afatinib) Mech Dacomitinib (PF-00299804) CRKL & EGFR Protein Prote MAPK14 & EGFR Protein Pro HSPB1 & EGFR Protein Prot EGFR & CTNNA1 Protein Pro EGFR & EGF Protein Protei EGFR & ERBB2 Protein Prot EGFR & PIK3R3 Protein Pro EGFR & PIK3R1 Protein Pro EGFR & CDH1 Protein Prote EGFR & FOS Protein Protei

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#28188446   2017/02/11 Save this To Up

Treatment Options for EGFR T790M-Negative EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer.

The introduction of first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib and afatinib) for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC) has dramatically improved patients' prognosis and quality of life (QoL). Unfortunately, after an initial and sometimes durable benefit from EGFR-TKI therapy, all patients with EGFR-mutant lung cancer eventually become resistant to the treatment and experience disease progression. In approximately 50% of these patients, genomic alterations in the EGFR kinase domain resulting in the mutant T790M are responsible for the resistance and this has led to the development of novel EGFR inhibitors active against mutant-T790M EGFR. The remaining 50% of patients with acquired resistance (AR) to EGFR-TKIs do not harbour the T790M mutation. In these cases, other mechanisms are involved in the development of AR such as perturbations of downstream pathways (e.g. K-RAS mutations), activation of alternative bypassing pathways (including c-Met, AXL, PIK3CA, BRAF), or histologic transformation. This review summarizes the main treatment strategies for this particular and heterogeneous group of "T790M-negative" patients.

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#28177428   2017/02/08 Save this To Up

Monitoring of somatic mutations in circulating cell-free DNA by digital PCR and next-generation sequencing during afatinib treatment in patients with lung adenocarcinoma positive for EGFR activating mutations.

Analysis of circulating cell-free DNA (cfDNA) is under intensive investigation for its potential to identify tumor somatic mutations. We have now explored the usefulness of such liquid biopsy testing with both the digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) during treatment of patients with the epidermal growth factor receptor (EGFR) inhibitor afatinib.

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Multiple lung carcinoma ( BIBW-2992 (Afatinib) Mech Lung squamous cell carcin Lung adenocarcinoma and n Lung adenocarcinoma tissu Small cell lung carcinoma Non small cell lung carci Lung non small cell cance Lung adenocarcinoma tissu Non small cell lung carci Lung small cell carcinoma Lung adenocarcinoma tissu

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#28167215   2017/02/07 Save this To Up

Treatments for EGFR-mutant non-small cell lung cancer (NSCLC): The road to a success, paved with failures.

The discovery of epidermal growth factor receptor (EGFR) activating mutations in non-small cell lung cancer (NSCLC) and the success story of EGFR tyrosine kinases inhibitors (TKIs) have changed the paradigm of cancer therapy from empirical cytotoxic chemotherapy to molecular-targeted cancer therapy. As a result, EGFR TKI therapy, including gefitinib, erlotinib and afatinib, has become the standard therapy for NSCLC patients with EGFR activating mutation as first-line therapy. However, most patients inevitably progress despite initial dramatic and rapid response to EGFR TKIs and therefore during the last decade, a lot of efforts have been made to identify and overcome various resistance mechanisms. Fortunately, T790M secondary mutation, the main resistance mechanism, can be overcome by newly developed third-generation EGFR TKIs, such as osimertinib, while most combination trials trying to overcome resistance mechanisms other than T790M mutation have failed so far. To make it worse, spatial and temporal tumor heterogeneity and clonal selection or evolution are also identified in EGFR mutant NSCLC tumors. Nevertheless, advance of comprehensive and more sensitive molecular diagnostics and monitoring technology, such as next-generation sequencing and dynamic monitoring technology using circulating biomarker and development of new cancer medicine with different mechanisms from EGFR TKIs, especially immune checkpoint inhibitors, might affect or change the treatment paradigm of EGFR mutant NSCLC in the near future.

2091 related Products with: Treatments for EGFR-mutant non-small cell lung cancer (NSCLC): The road to a success, paved with failures.

Multiple lung carcinoma ( Non small cell lung carci Non small cell lung carci Non small cell lung carci Lung non small cell cance Non small cell lung carci High density non small ce Non small cell lung carci Non small cell lung carci Non small cell lung carci Non small cell lung carci Non small cell lung carci

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#28149764   2017/02/02 Save this To Up

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance.

Osimertinib, third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved in the US and EU for the treatment of EGFR mutant T790M-positive non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs, such as gefitinib, erlotinib and afatinib. Although exciting survival data and response rates have been registered in patients treated with this and other third-generation EGFR-TKIs, unfortunately acquired resistance still occurs after approximately 10 months. Mechanisms determining progression of disease are heterogeneous and not fully understood. EGFR-dependent resistance mechanisms (such as new EGFR mutations), bypass pathway activation [as erb-b2 receptor tyrosine kinase 2 (HER2) or MET amplification] and histological transformation [in small cell lung cancer (SCLC)] have been reported, similarly to previous generation TKIs. Here, we review principle mechanisms of innate and acquired resistance described in literature both in clinical and preclinical settings during NSCLC treatment with third-generation EGFR-TKIs.

1710 related Products with: Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance.

DiscoveryPak™ Receptor Lung non small cell cance Non-small cell lung cance Epidermal Growth Factor ( Epidermal Growth Factor ( IGF-1R Signaling Phospho- DiscoveryPak™ EGFR Tyro Small cell lung carcinoma Non small cell lung carci Non small cell lung carci Lung small cell carcinoma High density non small ce

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#28131317   2017/01/29 Save this To Up

An unexpected response to second line EGFR inhibitor in relapsing leptomeningeal carcinomatosis from lung adenocarcinoma raises questions on differential mechanisms of action of these agents.


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