scholarly journals Generation and Characterization of a New Preclinical Mouse Model of EGFR-Driven Lung Cancer with MET-Induced Osimertinib Resistance

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3441
Author(s):  
Maicol Mancini ◽  
Quentin-Dominique Thomas ◽  
Sylvia Bourdel ◽  
Laura Papon ◽  
Emilie Bousquet ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Tumor Burden ◽  
Advanced Lung Cancer ◽  
Compensatory Mechanism ◽  
Met Amplification ◽  
Egfr Mutated

Despite the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to treat advanced lung cancer harboring EGFR-activating mutations, the prognosis remains unfavorable because of intrinsic and/or acquired resistance. We generated a new state-of-the-art mouse strain harboring the human EGFRT790M/L858R oncogene and MET overexpression (EGFR/MET strain) that mimics the MET amplification occurring in one out of five patients with EGFR-mutated lung cancer that relapsed after treatment with osimertinib, a third-generation anti-EGFR TKI. We found that survival was reduced in EGFR/MET mice compared with mice harboring only EGFRT790M/L858R (EGFR strain). Moreover, EGFR/MET-driven lung tumors were resistant to osimertinib, recapitulating the phenotype observed in patients. Conversely, as also observed in patients, the crizotinib (anti-MET TKI) and osimertinib combination improved survival and reduced tumor burden in EGFR/MET mice, further validating the model’s value for preclinical studies. We also found that in EGFR/MET mice, MET overexpression negatively regulated EGFR activity through MIG6 induction, a compensatory mechanism that allows the coexistence of the two onco-genic events. Our data suggest that single EGFR or MET inhibition might not be a good therapeutic option for EGFR-mutated lung cancer with MET amplification, and that inhibition of both pathways should be the best clinical choice in these patients.

scholarly journals Use of liquid biopsy in monitoring therapeutic resistance in EGFR oncogene addicted NSCLC

2020 ◽  
Vol 1 (6) ◽  
pp. 391-400
Author(s):  
Marialucia Iacovino ◽  
Vincenza Ciaramella ◽  
Fernando Paragliola ◽  
Gabriella Suarato ◽  
Gesualdina Busiello ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Liquid Biopsy ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Small Cells ◽  
Lung Cancer Patients ◽  
Non Invasive ◽  
Epidermal Growth ◽  
Egfr Mutated

Liquid biopsy has emerged as a minimally invasive alternative to tumor tissue analysis for the management of lung cancer patients, especially for epidermal growth factor receptor (EGFR) oncogene addicted tumor. In these patients, despite the clear benefits of tyrosine kinase inhibitors therapy, the development of acquired resistance and progressive disease is inevitable in most cases and liquid biopsy is important for molecular characterization at resistance and, being non-invasive, may be useful for disease monitoring. In this review, the authors will focus on the applications of liquid biopsy in EGFR-mutated non small cells lung cancer at diagnosis, during treatment and at progression, describing available data and possible future scenarios.

scholarly journals Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy

Cells ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 212 ◽  
Author(s):  
Tatsuya Nagano ◽  
Motoko Tachihara ◽  
Yoshihiro Nishimura
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
T790m Mutation ◽  
Epidermal Growth ◽  
Egfr Mutated ◽  
Egfr Tki ◽  
Egfr Tkis

Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves the overall survival of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of EGFR-mutated NSCLC, especially in patients with EGFR exon 19 deletions or an exon 21 L858R mutation. However, almost all cases experience disease recurrence after 1 to 2 years due to acquired resistance. The EGFR T790M mutation in exon 20 is the most frequent alteration associated with the development of acquired resistance. Osimertinib—a third-generation EGFR-TKI—targets the T790M mutation and has demonstrated high efficacy against EGFR-mutated lung cancer. However, the development of acquired resistance to third-generation EGFR-TKI, involving the cysteine residue at codon 797 mutation, has been observed. Other mechanisms of acquired resistance include the activation of alternative pathways or downstream targets and histological transformation (i.e., epithelial–mesenchymal transition or conversion to small-cell lung cancer). Furthermore, the development of primary resistance through overexpression of the hepatocyte growth factor and suppression of Bcl-2-like protein 11 expression may lead to problems. In this report, we review these mechanisms and discuss therapeutic strategies to overcome resistance to EGFR-TKIs.

scholarly journals Tumor immune microenvironment in non-small cell lung cancer with EGFR mutation before and after EGFR-TKIs treatment

2021 ◽  
Author(s):  
chao wang ◽  
lihui liu ◽  
sini li ◽  
hua bai ◽  
jie wang
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Treatment Time ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Before And After ◽  
Almost All ◽  
Egfr Tkis

Lung cancer is the most common cancer and a leading cause of death from cancer in men and women in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are considered as the first-line treatment of EGFR mutated NSCLC. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, with a median PFS of 9-14 months. With the development of immunotherapy, people realize that the interaction between tumor immune microenvironment (TIME) and tumor cells can also affect EGFR-TKIs treatment. TIME contains a variety of elements and previous researches of TIME in EGFR-TKIs therapy on NSCLC are decentralized. Here, we review the characteristics of TIME in NSCLC from EGFR-TKIs therapy and its role in TKIs resistance.

scholarly journals Role of PARP1-mediated autophagy in EGFR-TKI resistance in non-small cell lung cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhimin Zhang ◽  
Xiaojuan Lian ◽  
Wei Xie ◽  
Jin Quan ◽  
Maojun Liao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Advanced Lung Cancer ◽  
Tki Resistance ◽  
Geo Dataset ◽  
Epidermal Growth

AbstractResistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has become the main clinical challenge of advanced lung cancer. This research aimed to explore the role of PARP1-mediated autophagy in the progression of TKI therapy. PARP1-mediated autophagy was evaluated in vitro by CCK-8 assay, clonogenic assay, immunofluorescence, and western blot in the HCC-827, H1975, and H1299 cells treated with icotinib (Ico), rapamycin, and AZD2281 (olaparib) alone or in combination. Our results and GEO dataset analysis confirmed that PARP1 is expressed at lower levels in TKI-sensitive cells than in TKI-resistant cells. Low PARP1 expression and high p62 expression were associated with good outcomes among patients with NSCLC after TKI therapy. AZD2281 and a lysosomal inhibitor reversed resistance to Ico by decreasing PARP1 and LC3 in cells, but an mTOR inhibitor did not decrease Ico resistance. The combination of AZD2281 and Ico exerted a markedly enhanced antitumor effect by reducing PARP1 expression and autophagy in vivo. Knockdown of PARP1 expression reversed the resistance to TKI by the mTOR/Akt/autophagy pathway in HCC-827IR, H1975, and H1299 cells. PARP1-mediated autophagy is a key pathway for TKI resistance in NSCLC cells that participates in the resistance to TKIs. Olaparib may serve as a novel method to overcome the resistance to TKIs.

Effect of loss of a chromosome 7 containing multiple copies of EGFR gene on acquired resistance to EGFR-TKIs in EGFR mutated NSCLC.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18091-e18091
Author(s):  
Koh Furugaki ◽  
Toshiki Iwai ◽  
Yoichiro Moriya ◽  
Kaori Fujimoto-Ouchi
Keyword(s):  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Chromosome 7 ◽  
Fish Analysis ◽  
High Concentration ◽  
Multiple Copies ◽  
Egfr Mutated ◽  
Egfr Tkis ◽  
Resistant Cells

e18091 Background: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show notable effects for non-small cell lung cancers (NSCLC) harboring EGFR activating mutations. However, almost all patients eventually acquire resistance to EGFR-TKIs within several years. The major mechanisms of acquired resistance are acquisition of a secondary EGFR mutation T790M and amplification of MET. However, the mechanisms of other resistance remain unclear. In this study, we established novel erlotinib-resistant NSCLC cells and examined their resistant mechanism. Methods: Resistant cells were established by continuously exposing EGFR mutated NSCLC cells HCC827 to 0.1, 1 or 10 μM of erlotinib in 96 well plates for three months. The resistant mechanisms were determined by direct sequence analysis and EGFR FISH analysis. Results: Resistant cells were emerged from 14/96 and 3/96 wells by 0.1 μM and 1 μM of erlotinib exposure, respectively. No resistant cells appeared in the wells of 10 μM of erlotinib. The IC50 values of these resistant cells were more than 100-fold higher than that of parental cells. No secondary mutation of T790M was detected in any of the resistant cells. Instead, we found that 13/17 resistant cells were dominated by EGFR not amplified cells and one of resistant cells B10 consisted of more than 99.9% of them, while the parental cells consisted of 2.5% of EGFR not amplified cells. Then, we isolated EGFR not amplified clone 4D8 from parental cells and found that this clone also had a resistance to erlotinib comparable to the resistant cells B10. Metaphase FISH analysis showed that EGFR amplified cells in parental cells had a chromosome 7 containing multiple copies of EGFR, while EGFR not amplified cells in B10 did not have it. Furthermore, we found that EGFR not amplified cells were constantly emerged from EGFR amplified clone isolated from parental cells under normal cell culture condition. Conclusions: Loss of a chromosome 7 containing multiple copies of EGFR causes acquired resistance in HCC827 cells when exposed to relatively low concentration of erlotinib, while high concentration of erlotinib deprives HCC827 cells of the chance of emergence of resistant cells.

scholarly journals Mechanisms of Resistance to EGFR TKIs and Development of a New Generation of Drugs in Non-Small-Cell Lung Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Takayuki Kosaka ◽  
Ei Yamaki ◽  
Akira Mogi ◽  
Hiroyuki Kuwano
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Clinical Problem ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Tkis

Gefitinib and erlotinib, which are epidermal growth factor receptor- (EGFR-) specific tyrosine kinase inhibitors (TKIs), are widely used as molecularly targeted drugs for non-small-cell lung cancer (NSCLC). Currently, the search forEGFRgene mutations is becoming essential for the treatment of NSCLC since these have been identified as predictive factors for drug sensitivity. On the other hand, in almost all patients responsive to EGFR-TKIs, acquired resistance is a major clinical problem. Mechanisms of acquired resistance reported in the past few years include secondary mutation of theEGFRgene, amplification of theMETgene, and overexpression of HGF; novel pharmaceutical agents are currently being developed to overcome resistance. This review focuses on these mechanisms of acquired resistance to EGFR-TKIs and discusses how they can be overcome.

scholarly journals MET Gene Dysregulation as a Promising Therapeutic Target in Lung Cancer—A Review

2021 ◽  
Vol 11 (12) ◽  
pp. 1370
Author(s):  
Paulina Terlecka ◽  
Paweł Krawczyk ◽  
Anna Grenda ◽  
Janusz Milanowski
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Molecular Abnormalities ◽  
Promising Therapeutic Target ◽  
Tumorigenic Activity ◽  
Nsclc Patients

Several molecular abnormalities in the MET gene have been identified, including overexpression, amplification, point mutations, and “skipping mutation” in exon 14. Even though deregulated MET signaling occurs rarely in non-small cell lung cancer (NSCLC), it possesses tumorigenic activity. Since the discovery of the significant role played by MET dysregulations in resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), many clinical trials have been focused on mechanisms underlying this acquired resistance. Therefore, new therapeutic strategies are being considered in the personalized therapy of NSCLC patients carrying MET abnormalities. First, MET kinase inhibitors (tepotinib and capmatinib) have been shown to be effective in the first and subsequent lines of treatment in NSCLC patients with “skipping mutations” in exon 14 of MET gene. In this article, the authors show the role of MET signaling pathway alterations and describe the results of clinical trials with MET inhibitors in NSCLC patients.

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