Design of Chimeric Histone Deacetylase- and Tyrosine Kinase-Inhibitors: A Series of Imatinib Hybrides as Potent Inhibitors of Wild-Type and Mutant BCR-ABL, PDGF-Rβ, and Histone Deacetylases†

2009 ◽  
Vol 52 (8) ◽  
pp. 2265-2279 ◽  
Author(s):  
Siavosh Mahboobi ◽  
Stefan Dove ◽  
Andreas Sellmer ◽  
Matthias Winkler ◽  
Emerich Eichhorn ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Kinase Inhibitors ◽  
Wild Type

scholarly journals Effect of Epigallocatechin-3-Gallate on EGFR Signaling and Migration in Non-Small Cell Lung Cancer

2021 ◽  
Vol 22 (21) ◽  
pp. 11833
Author(s):  
Cristina Minnelli ◽  
Laura Cianfruglia ◽  
Emiliano Laudadio ◽  
Mobbili Giovanna ◽  
Roberta Galeazzi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Egfr Signaling ◽  
Wild Type ◽  
Small Cell Lung ◽  
And Migration

The epidermal growth factor receptor (EGFR) is one of the most well-studied molecular targets in non-small cell lung cancer (NSCLC) and tyrosine kinase inhibitors have been shown to be effective in the treatment of advanced NSCLC. Nevertheless, the efficacy of tyrosine kinase inhibitors could be compromised by additional mutations in EGFR and compensatory activations of other pathways. Epigallocatechin-3-gallate (EGCG), the main bioactive molecule in green tea, acts as a tyrosine kinase inhibitor toward cancer cells overexpressing EGFR (wild-type). However, little information has been reported on the effect of EGCG on EGFR with activating mutations. In this study, we evaluated the ability of EGCG to inhibit EGFR signaling activation in three different NSCLC cell lines containing wild-type EGFR or EGFR with additional mutations. The effect on proliferation, apoptosis, migration, and vinculin expression was then studied. Overall, our results demonstrate that EGCG polyphenol inhibits cell proliferation and migration in NSCLC cell lines, although with different efficacy and mechanisms. These data may be of interest for an evaluation of the use of EGCG as an adjunct to NSCLC therapies.

Is there a benefit on survival of tyrosine-kinase inhibitors versus chemotherapy in first line in mutated EGFR patients with advanced non-small cell cancer (NSCLC)? A meta-analysis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18020-e18020
Author(s):  
Gaetan Des Guetz ◽  
Bernard Uzzan ◽  
Kader Chouahnia ◽  
Patrick Nicolas ◽  
Jean F. Morere
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Cell Cancer ◽  
Random Effect Model ◽  
Lung Neoplasm ◽  
Phase Iii ◽  
Wild Type ◽  
Effect Model

e18020 Background: Tyrosine-Kinase Inhibitors (TKIs) markedly improve Progression Free Survival (PFS) of advanced NSCLC patients mutated for Epidermal Growth Factor Receptor (EGFR). Results on Overall Survival (OS) are more questionable. Therefore, we performed a publication-based meta-analysis to further assess this issue. Methods: We did a PubMed query using keywords simultaneously (lung neoplasm, TKI, EGFR mutation, survival). We also searched for relevant abstracts in proceedings of ASCO, ESMO, WCLC annual meetings. We cross-checked all references from all articles. Only phase III randomized controlled trials comparing TKI and chemotherapy were included. We used EasyMA software. Results: The 6 eligible studies included 2223 patients (516 males, 1688 females, mostly Asian, median age 60 years, 2155 adenocarcinomas (97 %), 996 mutated tumors, 389 stage IIIB, 1572 Stage IV (71 %), 1989 never smokers (89.5 %). Four studies assessed gefitinib, 2 erlotinib. Chemotherapies were doublets including a platinum salt. Four studies included only mutated patients. Compared to chemotherapy, EGFR TKIs significantly improved PFS (HR=0.39, 95 % CI 0.28-0.53, random effect model). Conversely, OS was similar among patients who first received TKI or chemotherapy (HR=1.00, CI 0.83-1.22, fixed effect model). PFS was significantly worse among non mutated patients in the 2 studies including both mutated and wild-type EGFR patients, whereas OS was unchanged. Concerning side-effects, rash, diarrhoea and interstitial lung disease were significantly more frequent after TKI (RRs 5.00; 2.40 and 6.07). As expected, fatigue (RR 0.41), nausea/vomiting (0.19) and haematological disorders were all significantly more frequent after chemotherapy (RRs for neutropenia, thrombocytopenia and anaemia 0.08; 0.18 and 0.26). Conclusions: The major discrepancy between a markedly improved PFS and a similar OS after TKI compared with chemotherapy could be related to the high level of crossing-over between the 2 groups. We found no detrimental effect on OS of TKIs among wild-type patients.

Markers of sensitivity or resistance to tyrosine kinase inhibitors (TKIs) in NSCLC patients harboring wild type EGFR.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. e19086-e19086
Author(s):  
Paola Ulivi ◽  
Elisa Chiadini ◽  
Alessandra Dubini ◽  
Maurizio Puccetti ◽  
Marco Angelo Burgio ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Wild Type ◽  
Nsclc Patients

Chimerically designed HDAC- and tyrosine kinase inhibitors. A series of erlotinib hybrids as dual-selective inhibitors of EGFR, HER2 and histone deacetylases

MedChemComm ◽  
2012 ◽  
Vol 3 (7) ◽  
pp. 829 ◽  
Author(s):  
Thomas Beckers ◽  
Siavosh Mahboobi ◽  
Andreas Sellmer ◽  
Matthias Winkler ◽  
Emerich Eichhorn ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Histone Deacetylases ◽  
Kinase Inhibitors ◽  
Selective Inhibitors

Lung cancer-derived EGFR mutations affect responses to tyrosine kinase inhibitors, but not to monoclonal antibodies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3044-3044
Author(s):  
M. Dechant ◽  
M. Peipp ◽  
T. Schneider-Merck ◽  
T. Beyer ◽  
J. J. Lammerts van Bueren ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Immune Cell ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Wild Type ◽  
Western Blots

3044 Background: The epidermal growth factor receptor (EGFR) serves as a molecular target for novel cancer therapeutic approaches. Two groups of anti-EGFR agents are clinically most advanced: tyrosine kinase inhibitors (TKI) and EGFR antibodies. Recently, somatic mutations in the EGFR kinase domain were identified in tumors from lung cancer patients, which affected EGFR signaling and which correlated with responses to TKI therapy. Since interference with tumor cell signaling is also considered an important mechanism of action for therapeutic antibodies, we investigated the influence of these intracellular EGFR mutations on cell killing by EGFR antibodies, in comparison to TKI. Methods: For this purpose, we established an EGF-responsive, non-transformed cell line model for the three most common lung cancer-derived intracellular EGFR mutations L858R, G719S and delE746-A750. EGFR phosphorylation status was analyzed by Western Blots. MTT assays were performed to compare TKI gefitinib and erlotinib with antibodies C225 and 2F8 in their capacity to inhibit cell growth of wild type and mutated EGFR-transfectants. Impact of intracellular EGFR mutations on immune cell-mediated killing by EGFR antibodies was measured in classical 3 hours 51-chromium-release assays. Results: Mutated EGFR transfected cells were growth factor- responsive, and significantly more sensitive to both gefitinib and erlotinib than wild type (WT) EGFR expressing cells. However, anti-tumor effector functions of both EGFR-directed IgG1 antibodies—chimeric C225 and fully human 2F8—were not affected by the mutations. Conclusions: Intracellular mutations of EGFR may, therefore, be less relevant for EGFR antibodies than for TKI. No significant financial relationships to disclose.

scholarly journals Coexistence of KRAS mutation with mutant but not wild-type EGFR predicts response to tyrosine-kinase inhibitors in human lung cancer

2014 ◽  
Vol 111 (11) ◽  
pp. 2203-2204 ◽  
Author(s):  
A Choughule ◽  
R Sharma ◽  
V Trivedi ◽  
A Thavamani ◽  
V Noronha ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kras Mutation ◽  
Kinase Inhibitors ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Wild Type
Sign in / Sign up

Export Citation Format

Share Document