Resistance to tyrosine kinase-targeted therapy in lung cancer: Autophagy and metabolic changes

2018 ◽  
Vol 04 ◽  
Author(s):  
Olivier E Pardo
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Metabolic Changes

Resistance to tyrosine kinase-targeted therapy in lung cancer: Autophagy and metabolic changes

Meta Gene ◽  
2018 ◽  
Vol 17 ◽  
pp. S10
Author(s):  
Hongde Li ◽  
William B. Stokes ◽  
Emily Chater ◽  
Ewa Rupniewska ◽  
Rajat Roy ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Metabolic Changes

The role of microRNA in the molecular mechanisms of resistance to EGFR tyrosine kinase inhibitor treatment in NSCLC and the current perspective on its clinical applications

2017 ◽  
Vol 5 ◽  
pp. 45-58
Author(s):  
Adam Szpechciński ◽  
Mateusz Florczuk
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Regulatory Function ◽  
Cancer Tissue ◽  
Lung Carcinogenesis ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tkis

Non-small cell lung cancer (NSCLC) is the leading cause of death from cancer over the world. Currently, a large number of research studies are conducted to develop and implement new treatment strategies. Intensive efforts are also made to improve robustness of modern molecular diagnostics to identify more precisely specific genetic and epigenetic cancer features (predictive biomarkers) and adjust the most effective treatment options for individual patient (personalized therapy). So called targeted therapy based on using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is nowadays the most widely chosen form of personalized treatment in advanced NSCLC. Favorable response to treatment with EGFR TKIs depends on the presence of somatic mutations in EGFR gene, detectable in lung cancer tissue. The resistance to EGFR TKIs acquired by most patients during treatment is the main ob-stacle to overcome in NSCLC targeted therapy. miRNAs (microRNAs) are small, noncoding RNA molecules that play a keyrole in the regulation of basic cellular processes, includingdif-ferentiation, proliferation and apoptosis, by controllinggene expression at the posttranscriptional level.Deregulation of miRNA activity results in the loss of homeostasisand the development of a number of pathologies, includinglung cancer. During lung carcinogenesis, miRNAs exhibitdual regulatory function: they act as oncogenes or as tumour suppressors. Better understanding of epigenetic mechanisms re-gulating either the sensitivity or the resistance of NSCLC cells to EGFR TKIs, through activity of miRNAs, may become a breakthrough in targe-ted therapy of lung cancer. The dual regulatory role of miRNA in cancer might drive the further development of personalised therapies in NSCLC. Furthermore, stable forms of tumourrelated miRNAs are detectable in the peripheral blood of patients with NSCLC that offers the potential benefits of using extracellular miRNAs as part of the diagnostic evaluation of cancer.

scholarly journals New possibilities in the treatment of EGFR mutation-positive non-small-cell lung cancer patients after the progression on a 1st and 2nd generation EGFR tyrosine kinase inhibitors

2018 ◽  
Vol 20 (2) ◽  
pp. 50-54
Author(s):  
K K Laktionov ◽  
E V Reutova ◽  
L A Nelyubina ◽  
M Yu Pitkevich ◽  
M A Okruzhnova ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Gene ◽  
2Nd Generation

Targeted therapy has opened a new era in treatment of patients with non-small-cell lung cancer associated with mutations of the epidermal growth factor receptor (EGFR) gene. However, most patients after starting targeted therapy develop progression within 10-12 months. The basic mechanisms of acquired resistance are known, the secondary mutation in exon 20 of EGFR gene is the leading cause in more than a half of the cases. To detect this mutation is important to repeat molecular testing, that, consequently, requiring re-biopsy. Liquid biopsy is considered as an alternative to re-biopsy. Osimertinib is a third generation EGFR-tyrosine kinase inhibitor, possessing antitumor activity, both, in respect of T790M-positive tumors and of tumors with mutations in exons 18, 19 and 21. In the randomized AURA3 trial, the use of osimertinib was effective in 71% of patients, the median progression free survival was 11 months after the progression on1st-line targeted therapy and was statistically significant than in case of chemotherapy application. Patients with brain metastases also show response to osimertinib treatment. In our study, 29 patients received osimertinib after the progression on targeted therapy of the 1st and 2nd generation tyrosine kinase inhibitors. Objective response was reported in 44.8% (complete response - 3.4%), stabilization - 51.7% and progression - 3.5%. We will show the results concerning the time without progression in the near future. The tolerance of treatment is good. Osimertinib has been approved for 1st-line targeted therapy treatment of patients with the T790M mutation upon progression in Russian Federation, thus we have new opportunities to improve the results of the treatment in this group of patients.

scholarly journals Efficacy of EGFR TKI Targeted Therapy versus TKI in Combination with Chemotherapy in Non-Small-Cell Lung Cancer

2020 ◽  
Vol 3 ◽  
Author(s):  
Alaina Johnston ◽  
Takefumi Komiya
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival

Background and Hypothesis:  Non-Small Cell Lung Cancer (NSCLC) constitutes the largest proportion of lung cancers and is the foremost cause of mortality associated with cancer around the world. Of patients with non-small cell lung cancer, approximately 15% of Caucasians and 30% of Asians have activating mutations in the epidermal growth factor receptor (EGFR) gene. Numerous studies have indicated increased progression free survival after treatment with tyrosine kinase inhibitors (TKI). However, the most efficacious combination of drugs, whether TKIs, chemotherapy, or anti-angiogenesis, is still unknown. This literature review will be constructed to determine whether tyrosine kinase inhibitor targeted therapy in combination with chemotherapy or anti-angiogenesis drugs is more effective in prolonging progression free survival in EGFR-mutated NSCLC as opposed to tyrosine kinase inhibitor targeted therapy alone.    Project Methods:  The methodology of this proposed literature review is an online search of PubMed, Journal of Clinical Oncology, and important scientific conferences. The treatment interventions consist of tyrosine kinase inhibitor targeted therapy in combination with chemotherapy and tyrosine kinase inhibitor targeted therapy alone. The projected outcome is an increase in progression free survival and overall survival. The proposed data analysis consists of constructing a forest plot in order to display the results.    Results:  The results are expected to support the hypothesis, that combination treatment with TKI and chemotherapy will allow patients with an opportunity to prolong their progression-free survival. The forest plot is expected to indicate a progression-free survival hazard ratio that favors combination therapy. P-values will be included to indicate statistically significant results.    Conclusion and Potential Impact:  The importance of finding the answer to this hypothesis is that it will improve treatment outcomes for patients with NSCLC. It will provide patients with a strong alternative to chemotherapy or tyrosine kinase inhibitor therapy alone. Most importantly, it will provide patients with an avenue to increase their progression-free survival. 

BATTLE (Biomarker-based Approach of Targeted Therapy for Lung Cancer Elimination)

2010 ◽  
Author(s):  
Waun K. Hong ◽  
Roy Herbst ◽  
Edward Kim
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy

scholarly journals Potential treatment for chronic myeloid leukemia using microRNA: in silico comparison between plants and human microRNAs in targeting BCR-ABL1 gene

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Syarifah Faezah Syed Mohamad ◽  
Marjanu Hikmah Elias
Keyword(s):  
Targeted Therapy ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Pathway Analysis ◽  
Protein Interaction ◽  
Protein Interaction Network ◽  
In Silico ◽  
Myeloid Leukemia ◽  
Interaction Network ◽  
Folding Energy

Abstract Background Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the expression of the BCR-ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) are used to treat CML, but mutations in the tyrosine kinase domain contribute to CML chemo-resistance. Therefore, finding alternative molecular-targeted therapy is important for the comprehensive treatment of CML. MicroRNAs (miRNA) are small non-coding regulatory RNAs which suppress the expression of their target genes by binding to the 3′ untranslated region (3′UTR) of the target mRNA. Hypothetically, the miRNA-mRNA interaction would suppress BCR-ABL1 expression and consequently reduce and inhibit CML cell proliferation. Thus, our objective was to determine the target interaction of human and plant miRNAs targeting the 3′UTR region of BCR-ABL1 in terms of miRNA binding conformity, protein interaction network, and pathways using in silico analysis. The 3′UTR sequence of BCR-ABL1 is obtained from Ensembl Genome Browser while the binding conformity was determined using the PsRNATarget Analysis Server, RNA22, Target Rank Server, and DIANA TOOLS. Protein-protein interaction network and pathway analysis are determined using STRING, Cytoscape, and KEGG pathway analysis. Results Five plants and five human miRNAs show strong binding conformity with 3′UTR of BCR-ABL1. The strongest binding conformity was shown by Oryza sativa’s Osa-miR1858a and osa-miR1858b with −24.4 kcal/mol folding energy and a p value of 0.0077. Meanwhile, in human miRNA, the hsa-miR-891a-3p shows the highest miTG score of 0.99 with −12 kcal/mol folding energy and a p value of 0.037. Apart from ABL1, osa-miR1858a/osa-miR1858b and hsa-miR891a-3p also target other 720 and 645 genes, respectively. The interaction network of Osa-miR1858a/osa-miR1858b and hsa-miR891a-3p identifies nineteen and twelve ABL1’s immediate neighboring proteins, respectively. The pathways analysis focuses on the RAS, MAPK, CML, and hematopoietic cell lineage pathway. Conclusion Both plant and human miRNAs tested in this study could be a potential therapeutic prospect in CML treatment, but thermodynamically, osa-miR1858a/osa-miR1858b binding to ABL1 is more favorable. However, it is important to carry out more research in vitro and in vivo and clinical studies to assess its efficacy as a targeted therapy for CML. Graphical abstract

scholarly journals Drug Tolerance to EGFR Tyrosine Kinase Inhibitors in Lung Cancers with EGFR Mutations

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1590
Author(s):  
Kenichi Suda ◽  
Tetsuya Mitsudomi
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Drug Tolerance ◽  
Lung Cancers ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Mutated

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard of care for the first-line treatment of patients with lung cancers with EGFR-activating mutations. However, the acquisition of resistance to EGFR TKIs is almost inevitable, with extremely rare exceptions, and drug-tolerant cells (DTCs) that demonstrate reversible drug insensitivity and that survive the early phase of TKI exposure are hypothesized to be an important source of cancer cells that eventually acquire irreversible resistance. Numerous studies on the molecular mechanisms of drug tolerance of EGFR-mutated lung cancers employ lung cancer cell lines as models. Here, we reviewed these studies to generally describe the features, potential origins, and candidate molecular mechanisms of DTCs. The rapid development of an optimal treatment for EGFR-mutated lung cancer will require a better understanding of the underlying molecular mechanisms of the drug insensitivity of DTCs.

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