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

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.

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

Cells ◽

10.3390/cells7110212 ◽

2018 ◽

Vol 7 (11) ◽

pp. 212 ◽

Cited By ~ 49

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.

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Effective assessment of low times MET amplification in pleural effusion after epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) acquired resistance

Medicine ◽

10.1097/md.0000000000009021 ◽

2018 ◽

Vol 97 (1) ◽

pp. e9021 ◽

Cited By ~ 6

Author(s):

Chang-guo Wang ◽

Da-xiong Zeng ◽

Jian-an Huang ◽

Jun-hong Jiang

Keyword(s):

Epidermal Growth Factor Receptor ◽

Receptor Tyrosine Kinase ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Met Amplification ◽

Epidermal Growth ◽

Effective Assessment ◽

Egfr Tkis ◽

Receptor Tyrosine Kinase Inhibitors

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

10.22541/au.161393354.40757172/v1 ◽

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.

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

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/165214 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 65

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.

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The Journey of an EGFR-Mutant Lung Adenocarcinoma through Erlotinib, Osimertinib and ABCP Immunotherapy Regimens: Sensitivity and Resistance

Case Reports in Oncology ◽

10.1159/000503417 ◽

2019 ◽

Vol 12 (3) ◽

pp. 765-776 ◽

Cited By ~ 4

Author(s):

Albina Kibirova ◽

Malcolm D. Mattes ◽

Matthew Smolkin ◽

Patrick C. Ma

Keyword(s):

Kinase Inhibitors ◽

Egfr Mutation ◽

Tumor Response ◽

Checkpoint Inhibitors ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Epidermal Growth ◽

Egfr Mutant ◽

Egfr Tkis ◽

Guided Therapy

Patients with epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) have several EGFR targeting tyrosine kinase inhibitors (TKIs) available in frontline management. However, the disease will inevitably progress over time due to acquired resistance. Longitudinal tumor profiling for genomics guided therapy is indicated upon disease progression. It is a common scenario yet, when after failure of EGFR-TKIs, potentially actionable genomic alterations are lacking. Management of such patient is challenging with very limited options available. Combination of chemotherapy, anti-vascular/anti-angiogenic and immune-checkpoint inhibitors may become a salvage option for such patients. Here we describe a case of TKI refractory EGFR-mutant NSCLC successfully treated with carboplatin, paclitaxel, atezolizumab and bevacizumab combination with remarkable prompt tumor response.

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Prior acquired resistance to paclitaxel relays diverse EGFR-targeted therapy persistence mechanisms

Science Advances ◽

10.1126/sciadv.aav7416 ◽

2020 ◽

Vol 6 (6) ◽

pp. eaav7416 ◽

Cited By ~ 2

Author(s):

Mark Borris D. Aldonza ◽

Jayoung Ku ◽

Ji-Young Hong ◽

Donghwa Kim ◽

Seung Jung Yu ◽

...

Keyword(s):

Cancer Cells ◽

Kinase Inhibitors ◽

Clonal Evolution ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Cancer Recurrence ◽

Resistant Cell ◽

Small Scale ◽

Primary Resistance ◽

Egfr Tkis

Secondary drug resistance stems from dynamic clonal evolution during the development of a prior primary resistance. This collateral type of resistance is often a characteristic of cancer recurrence. Yet, mechanisms that drive this collateral resistance and their drug-specific trajectories are still poorly understood. Using resistance selection and small-scale pharmacological screens, we find that cancer cells with primary acquired resistance to the microtubule-stabilizing drug paclitaxel often develop tolerance to epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs), leading to formation of more stable resistant cell populations. We show that paclitaxel-resistant cancer cells follow distinct selection paths under EGFR-TKIs by enriching the stemness program, developing a highly glycolytic adaptive stress response, and rewiring an apoptosis control pathway. Collectively, our work demonstrates the alterations in cellular state stemming from paclitaxel failure that result in collateral resistance to EGFR-TKIs and points to new exploitable vulnerabilities during resistance evolution in the second-line treatment setting.

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Clinical Definition of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.24.7049 ◽

2010 ◽

Vol 28 (2) ◽

pp. 357-360 ◽

Cited By ~ 498

Author(s):

David Jackman ◽

William Pao ◽

Gregory J. Riely ◽

Jeffrey A. Engelman ◽

Mark G. Kris ◽

...

Keyword(s):

Tyrosine Kinase ◽

Somatic Mutations ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Small Cell Lung ◽

Epidermal Growth ◽

Definition Of ◽

Egfr Tki ◽

Egfr Tkis

Ten percent of North American patients with non–small-cell lung cancer have tumors with somatic mutations in the gene for the epidermal growth factor receptor (EGFR). Approximately 70% of patients whose lung cancers harbor somatic mutations in exons encoding the tyrosine kinase domain of EGFR experience significant tumor regressions when treated with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, the overwhelming majority of these patients inevitably acquire resistance to either drug. Currently, the clinical definition of such secondary or acquired resistance is not clear. We propose the following criteria be used to define more precisely acquired resistance to EGFR TKIs. All patients should have the following criteria: previous treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib); either or both of the following: a tumor that harbors an EGFR mutation known to be associated with drug sensitivity or objective clinical benefit from treatment with an EGFR TKI; systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or WHO) while on continuous treatment with gefitinib or erlotinib within the last 30 days; and no intervening systemic therapy between cessation of gefitinib or erlotinib and initiation of new therapy. The relatively simple definition proposed here will lead to a more uniform approach to investigating the problem of acquired resistance to EGFR TKIs in this unique patient population. These guidelines should minimize reporting of false-positive and false-negative activity in these clinical trials and would facilitate the identification of agents that truly overcome acquired resistance to gefitinib and erlotinib.

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Cytotoxic chemotherapy may overcome the development of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) therapy

Lung Cancer ◽

10.1016/j.lungcan.2015.06.016 ◽

2015 ◽

Vol 89 (3) ◽

pp. 287-293 ◽

Cited By ~ 22

Author(s):

Shintaro Kanda ◽

Hidehito Horinouchi ◽

Yutaka Fujiwara ◽

Hiroshi Nokihara ◽

Noboru Yamamoto ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Receptor Tyrosine Kinase ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Cytotoxic Chemotherapy ◽

Epidermal Growth ◽

Egfr Tkis ◽

Receptor Tyrosine Kinase Inhibitors

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

Exploration of Targeted Anti-tumor Therapy ◽

10.37349/etat.2020.00024 ◽

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.

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