scholarly journals Clinical Benefit of Tyrosine Kinase Inhibitors in Advanced Lung Cancer with EGFR ‐G719A and Other Uncommon EGFR Mutations

2020 ◽  
Author(s):  
Kartik Sehgal ◽  
Deepa Rangachari ◽  
Paul A. VanderLaan ◽  
Susumu S. Kobayashi ◽  
Daniel B. Costa
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Clinical Benefit ◽  
Kinase Inhibitors ◽  
Egfr Mutations ◽  
Advanced Lung Cancer

scholarly journals Lung Cancer: Biomarkers, Tyrosine Kinase Inhibitors and Monoclonal Antibodies

2017 ◽  
Vol 1 (2) ◽  
pp. 41
Author(s):  
Made Putra Semadhi ◽  
Stefanus Layli Prasojo ◽  
Anandani Widarini
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Excision Repair ◽  
Neuron Specific Enolase ◽  
Egfr Mutations ◽  
Ca 125 ◽  
Cytokeratin 19 ◽  
Dna Mutation

Lung cancer is the most contributor of cancer cause death in the world. Lung cancer is related to cigarette consumption and genetic factor. Nicotine derived nitrosamine ketone is the most important inducer of lung cancer associated with DNA Mutations resulting in the activation of Kirsten rat sarcoma viral (KRAS) oncogenes. DNA Mutation in Lung cancer is mostly presence by epidermal growth factor receptor (EGFR) mutations. There were seven potential biomarkers to detect early lung cancer, whereas carcinoembryonic antigen (CEA), neuron specific enolase (NSE), cytokeratin-19 fragments (CYFRA 21-1), alpha-fetoprotein (AFP), cancer antigen 125 (CA-125), CA-199 and ferritin. The use of biomarkers in combination can improve the accuracy in diagnosing lung cancer. Other biomarkers include KRAS mutations, B-type Raf kinase (BRAF) mutation, mesenchymal-epithelial transition factor (MET) amplification and Excision repair cross-complementing group 1 (ERCC1) can be used to see whether there are any genetic mutations that lead to lung cancer. Treatment of lung cancer with chemotherapy can be done using tyrosine kinase inhibitors and monoclonal antibodies.Keywords: lung cancer, DNA mutation, EGFR, KRAS, BRAF, MET, tyrosine kinase 

scholarly journals Effective Tyrosine Kinase Inhibitors result in the intracellular accumulation of EGFR and allows response prediction in patients

2019 ◽  
Author(s):  
Maurice de Wit ◽  
Ya Gao ◽  
Darlene Mercieca ◽  
Iris de Heer ◽  
Bart Valkenburg ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Conformational Changes ◽  
Clinical Benefit ◽  
Kinase Inhibitors ◽  
Response Prediction ◽  
Egfr Mutations ◽  
Tumor Type ◽  
Intracellular Accumulation ◽  
Egfr Tkis

AbstractClinical responses to EGFR tyrosine kinase inhibitors are restricted only to tumors harboring specific activating mutations and even then, not all tyrosine kinase inhibitors provide clinical benefit. We here show that the addition of EGFR-TKIs results in a strong and rapid intracellular accumulation of the protein. However, this accumulation was observed only in the context of a combination of a TKI-sensitive mutation with a clinically effective TKI: TKI-insensitive mutations did not show this accumulation nor did clinically ineffective TKIs induce accumulation. All TKIs effectively inhibited EGFR phosphorylation and downstream pathway activation, irrespective of the mutation present in EGFR. The discrepancy between molecular activity of TKIs and their efficacy in patients therefore is mimicked by the mutation- and TKI-specificity of intracellular accumulation. Using this intracellular accumulation as assay, we were able to predict response to gefitinib in a panel of cell-lines (harboring different EGFR mutations) and predicted clinical benefit to EGFR TKIs on a cohort of unselected pulmonary adenocarcinoma patients (hazard ratio 0.21, P=0.0004). Even in patients harboring rare mutations with unknown TKI-sensitivity, intracellular accumulation was predictive of the clinical response. The intracellular accumulation depended on a continued presence of TKI indicating that TKIs exert a continued effect on the protein even after its dephosphorylation. It is therefore possible that accumulation is caused by conformational changes induced by both the mutation and the TKI and this change induces a block in intracellular trafficking. Interestingly, intracellular accumulation was observed independent of the genetic background of the cell, indicating that accumulation is almost entirely dictated by the combination of mutation and TKI. Our results therefore suggest that TKI-sensitivity is tumor-type independent.

Identification of RET fusion as mechanisms of resistance to EGFR tyrosine-kinase inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21074-e21074
Author(s):  
Zhongxing Bing ◽  
Weiran Wang ◽  
Danhua Wang ◽  
Tonghui Ma
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Next Generation Sequencing Data ◽  
Egfr Mutations ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki ◽  
Egfr Tkis

e21074 Background: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their characteristics acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed next-generation sequencing data of EGFR+ lung cancer patients, and 8 patients were identified coexisting of EGFR mutations and RET fusion. Their treatment history was collected. Results: The co-occurrence of RET fusion with EGFR oncogenic variations was observed in eight patients, and all of the 8 patients have received previous EGFR-TKI treatment. EGFR mutations were including 4 L858R mutations, 4 exon 19 deletions, and 6 T790M mutations. And the partner genes of RET identified by NGS were including TRIM33 (2/8), GPRC6A (1/8), TLN1 (1/8), KIAA1598 (1/8), SPECC1 (1/8), TRIM24 (1/8) and CCDC6 (1/8). The allelic fractions (AFs) of first-generation EGFR-TKI sensitizing mutations were higher than AFs of EGFR T790M mutations as well as AFs of RET fusion. These RET fusions are fused with rare partner genes, rather than the most common KIF5B in lung cancer. Conclusions: This study extended the knowledge of RET fusion as resistance mechanism to EGFR TKIs in lung cancer. The detection of RET fusions may uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches.[Table: see text]

Tyrosine kinase inhibitors in the treatment of advanced lung cancer from example of preferential medicine provision in Moscow city

2020 ◽  
Vol 30 (4) ◽  
pp. 463-472
Author(s):  
D. A. Andreev ◽  
A. A. Zav'yalov ◽  
K. I. Polyakova ◽  
M. V. Davydovskaуa
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Advanced Lung Cancer ◽  
Small Cell Lung ◽  
Moscow City

Lung cancer is leading cause of death across oncological diseases. Nowadays, the therapy of lung cancer remains most serious problem of oncology. Targeted therapy including tyrosine kinase inhibitors (TKIs) is widely used in current clinical practice to treat advanced or metastatic non-small cell lung cancer. This paper reviews the clinical aspects of TKIs application in practical medicine. The article summarizes the results and outcomes of key clinical trials focused on efficiency and safety of TKIs, describes the results of analysis for TKIs need within the Moscow City Department of Healthcare system providing preferential medicines. The perspectives of future clinical developments of targeted treatments for lung cancer are postulated and discussed as well. Our previously unpublished data clearly demonstrate that gefitinib, erlotinib and afatinib turned out to be the most used TKIs for treatment of non-small cell lung cancer in the system of preferential medicine supply for Moscow population in 2018. The choice of targeted drugs directly depends on the molecular genetic profile of the tumor. To further improve the use of financial resources of the Moscow City Department of Healthcare it is essential to define accurately the molecular profile of the tumor specimens and prescribe the most effective TKIs for each individual case of lung cancer.

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.

Sign in / Sign up

Export Citation Format

Share Document