scholarly journals Inhibition of the FGF/FGFR System Induces Apoptosis in Lung Cancer Cells via c-Myc Downregulation and Oxidative Stress

2020 ◽  
Vol 21 (24) ◽  
pp. 9376
Author(s):  
Arianna Giacomini ◽  
Sara Taranto ◽  
Sara Rezzola ◽  
Sara Matarazzo ◽  
Elisabetta Grillo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Lung Tumor ◽  
Growth Factor Receptor ◽  
Therapeutic Benefit ◽  
Dependent Lung ◽  
Lung Cancers ◽  
Molecular Features ◽  
Promising Therapeutic Approach

Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers.

Lung Cancer in 2013: State of the Art Therapy for Metastatic Disease

2013 ◽  
pp. 339-346
Author(s):  
Frances A. Shepherd ◽  
Paul A. Bunn ◽  
Luis Paz-Ares
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Poor Performance ◽  
Initial Therapy ◽  
Egfr Mutations ◽  
Molecular Testing ◽  
Molecular Features ◽  
Platinum Doublet

Lung cancer is the leading worldwide cause of cancer death and the majority of patients present with metastatic stage IV disease. At diagnosis, clinical, histologic, and molecular features must be considered in therapeutic decision-making for systemic therapy. Molecular testing for at least epidermal growth factor receptor ( EGFR) and ALK should be performed in all patients before therapy. Platinum doublet chemotherapy may be considered for “fit” patients who do not have a molecular driver genetic abnormality. Bevacizumab can be considered for addition to the doublet in patients with nonsquamous cancers who have no contraindications. A pemetrexed combination is considered only in nonsquamous histology. Patients with EGFR mutations or ALK fusions should be treated with erlotinib or crizotinib, respectively, even in patients with tumor-related poor performance. The tyrosine-kinase inhibitors (TKIs) may be continued until multisite, symptomatic progression. For patients initially treated with a platinum doublet, maintenance chemotherapy with pemetrexed, erlotinib, gemcitabine, or possibly docetaxel is an option with selection based on clinical features, histology, type of initial therapy, and response to first-line therapy.

scholarly journals STAT3 induces G9a to exacerbate HER3 expression for the survival of epidermal growth factor receptor-tyrosine kinase inhibitors in lung cancers

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yi-Fang Chang ◽  
Ken-Hong Lim ◽  
Ya-Wen Chiang ◽  
Zong-Lin Sie ◽  
Jungshan Chang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Lung Cancer Cell ◽  
Lung Cancers ◽  
Her3 Expression ◽  
Epidermal Growth ◽  
Egfr Tki

Abstract Background HER3 mediates drug resistance against epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers. Previously, we demonstrated that EGFR induces HER3 overexpression, which facilitates the formation of cancer stem-like tumorspheres. However, the cellular mechanism through which EGFR regulates HER3 expression remains unclear. We hypothesized that EGFR downstream of STAT3 participates in HER3 expression because STAT3 contributes to cancer stemness and survival of EGFR-TKI resistant cancers. Methods First, RNAseq was used to uncover potential genes involved in the formation of lung cancer HCC827-derived stem-like tumorspheres. EGFR-positive lung cancer cell lines, including HCC827, A549, and H1975, were individually treated with a panel containing 172 therapeutic agents targeting stem cell-associated genes to search for potential agents that could be applied against EGFR-positive lung cancers. In addition, gene knockdown and RNAseq were used to investigate molecular mechanisms through which STAT3 regulates tumor progression and the survival in lung cancer. Results BBI608, a STAT3 inhibitor, was a potential therapeutic agent that reduced the cell viability of EGFR-positive lung cancer cell lines. Notably, the inhibitory effects of BBI608 were similar with those associated with YM155, an ILF3 inhibitor. Both compounds reduced G9a-mediated HER3 expression. We also demonstrated that STAT3 upregulated G9a to silence miR-145-5p, which exacerbated HER3 expression in this study. Conclusions The present study revealed that BBI608 could eradicate EGFR-positive lung cancers and demonstrated that STAT3 enhanced the expression of HER3 through miR-145-5p repression by G9a, indicating that STAT3 is a reliable therapeutic target against EGFR-TKI-resistant lung cancers.

scholarly journals Retrospective study on the clinicogenomic characteristics of EGFR mutant and wildtype NSCLC

2020 ◽  
Author(s):  
Chirag Dhar
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Receptor Gene ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Asian Ethnicity ◽  
Lung Cancers ◽  
Cohort Study Design ◽  
Underlying Mechanisms ◽  
Egfr Mutant

Background: Lung cancer is among the leading causes of mortality. Nearly 90% of all lung cancers are histologically classified as non-small cell lung cancer (NSCLC). A subset of these tumors harbor mutations on the epidermal growth factor receptor gene (EGFR) and such patients are candidates for targeted therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs). Aim: To compare and contrast the clinicogenomic characteristics of EGFR mutant and wildtype NSCLC. Methods and results: A retrospective cohort study design was used to analyze publicly available data on cBioPortal.org. Patients with EGFR mutations were more likely to be, female; of Asian ethnicity; never-smokers and diagnosed with lung adenocarcinoma. Metastasis to, the pleura; pleural fluid and liver were common in patients with EGFR mutant NSCLC. On the other hand, lymph node, brain and adrenal gland metastases were more common in patients with other mutations. While the median overall survival was about the same in the two groups, progression free survival was significantly shorter in the EGFR mutant group. The mutational landscape was significantly different in the two groups with EGFR mutant NSCLCs having a lower mutational burden. Differences in copy number alterations between the two groups were also noted. Conclusions: The clinicogenomic profiles of EGFR mutant and wildtype significantly differ. Further studies on these differences and underlying mechanisms are likely to lead to new druggable targets that overcome EGFR TKI resistance.

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.

Chitosan-derived Nanoparticles Impede Signal Transduction for T790M Lung Cancer Therapy

2021 ◽  
Author(s):  
Guojun Huang ◽  
Qi Chen ◽  
Jiawei Hu ◽  
Jianming Mao ◽  
Yunhong He ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
T790m Mutation ◽  
Develop Disease Progression ◽  
Lung Cancer Therapy ◽  
Epidermal Growth ◽  
Egfr Tkis ◽  
Receptor Tyrosine Kinase Inhibitors

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treated patients ultimately develop disease progression, about 50% of which involved in the emergence of a T790M mutation acquiring drug resistance. In...

scholarly journals Tobacco Smoke–Induced Lung Cancer in Animals—A Challenge to Toxicology (?)

2007 ◽  
Vol 26 (4) ◽  
pp. 339-344 ◽  
Author(s):  
Hanspeter Witschi
Keyword(s):  
Lung Cancer ◽  
Tobacco Smoke ◽  
Lung Tumor ◽  
Distant Metastases ◽  
Female Rats ◽  
Chemopreventive Agents ◽  
Lung Cancers ◽  
Malignant Lesions ◽  
Product Modification ◽  
Rats And Mice

Tobacco smoke is a known human carcinogen that primarily produces malignant lesions in the respiratory tract, although it also affects multiple other sites. A reliable and practical animal model of tobacco smoke–induced lung cancer would be helpful for in studies of product modification and chemoprevention. Over the years, many attempts to reproduce lung cancer in experimental animals exposed to tobacco smoke have been made, most often with negative or only marginally positive results. In hamsters, malignant lesions have been produced in the larynx, but not in the deeper lung. Female rats and female B6C3F1 mice, when exposed over lifetime to tobacco smoke, develop tumors in the nasal passages and also in the lung. Contrary to what is seen in human lung cancers, most rodent tumors are located peripherally and only about half of them show frank malignant features. Distant metastases are extremely rare. Male and female strain A mice exposed to 5 months to tobacco smoke and then kept for another 4 months in air respond to tobacco smoke with increased lung tumor multiplicities. However, the increase over background levels is comparatively small, making it difficult to detect significant differences when the effects of chemopreventive agents are evaluated. On the other hand, biomarkers of exposure and of effect as well as evaluation of putative carcinogenic mechanisms in rats and mice exposed to tobacco smoke allow detection of early events and their modification by different smoke types or chemopreventive agents. The challenge will be to make such data broadly acceptable and accepted in lieu of having to do more and more long term studies involving larger and larger number of animals.

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