Drug Resistance to EGFR Inhibitors in Lung Cancer

Tetsu, Osamu; Hangauer, Matthew J.; Phuchareon, Janyaporn; Eisele, David W.; McCormick, Frank

doi:10.1159/000443368

Cited by 63 publications

(51 citation statements)

References 129 publications

(226 reference statements)

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“…Nearly 50% of these patients fail due to the fact that chemotherapy cannot prevent a relapse. Reasons for treatment failure are an intrinsic resistance or the development of an acquired resistance under treatment [24]. Active drug efflux transporters of the adenosine triphosphate binding cassette (ABC) are involved in transport processes for a variety of drugs used in chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Induces Multidrug Resistance via Enhancement of Epidermal Growth Factor-Like Domain 7 Expression in Non-Small Lung Cancer Cells

Shen

Zhi²,

Wang³

et al. 2017

Chemotherapy

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Chemotherapy is widely used in non-small cell lung cancer (NSCLC) treatment, yet multidrug resistance (MDR) is a major chemotherapeutic obstacle in both resectable and advanced NSCLC. Epidermal growth factor-like domain 7 (EGFL7), also known as vascular endothelial stain, is an endothelial cell-derived secreted factor that regulates vascular tube formulation. The aim of this study was to investigate the potential relationships between EGFL7 and MDR in NSCLC cells. We first obtained the CDDP-based MDR phenotype cell line A549/CDDP by repeated exposure to a proper concentration of CDDP (cisplatin) from original A549 cells. These A549/CDDP cells, which maintained relative high levels of EGFL7 and P-glycoprotein (P-gp), were resistant to other chemotherapy drugs, such as carboplatin (CBP), paclitaxel (TAX), and gemcitabine (GEM) (p < 0.05). We also found that hypoxia significantly reduced the chemosensitivity of NSCLC cells, and hypoxia-induced MDR was mediated by P-gp and EGFL7 (p < 0.05). EGFL7 was veryy relevant to NSCLC cell MDR, and downregulation of EGFL7 could significantly increase the chemosensitivity of NSCLC cells (p < 0.05). Thus, our findings first indicate that hypoxia induced NSCLC cell MDR at least partly by enhancing the expression of EGFL7 protein. EGFL7 might be a feasible target for reversing hypoxia-mediated MDR in NSCLC cells and a promising biomarker for predicting the development of MDR in NSCLC patients on chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Hypoxia Induces Multidrug Resistance via Enhancement of Epidermal Growth Factor-Like Domain 7 Expression in Non-Small Lung Cancer Cells

Shen

Zhi²,

Wang³

et al. 2017

Chemotherapy

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“…Second, afatinib has the potential to affect NSCLC, which is resistant to gefitinib and erlotinib. In recent years, drug resistance has become a substantial issue [27]. The study of LUX-Lung 4 demonstrated that some patients who had acquired resistance to gefitinib and/or erlotinib could receive benefit from afatinib, with a median progression-free survival of 4.4 months and an objective response rate of 8.2% [28].…”

Section: Discussionmentioning

confidence: 99%

Clinical Efficacy of Afatinib Treatment for a Patient with Leptomeningeal Carcinomatosis

Kawaguchi

Hanaoka²,

Hayashi³

et al. 2016

Chemotherapy

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Leptomeningeal metastases occur in 1% of patients with non-small-cell lung cancer. There have been several reports on the treatment of leptomeningeal metastases with afatinib. Our patient was a 41-year-old woman who had never smoked and was diagnosed with stage IV adenocarcinoma of the lung with an epidermal growth factor receptor (EGFR) mutation. She was treated with afatinib for the recurrence of leptomeningeal metastases. After the treatment with afatinib was initiated, the neurological symptoms dramatically regressed, and she achieved progression-free survival for 7 months. The concentration of afatinib in the cerebrospinal fluid (CSF) ranged from 0.05 to 0.14 ng/mL, and the penetration rate of afatinib from the plasma to the CSF ranged from 0.28 to 0.40%. This concentration might be sufficient to achieve a clinical effect for leptomeningeal carcinomatosis. Therefore, afatinib administered at the usual doses may be an effective treatment for leptomeningeal carcinomatosis of EGFR-mutated or EGFR-tyrosine kinase inhibitor-sensitive lung adenocarcinoma.

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“…6 Acquired resistance mechanisms to the firstand second-generation EGFR TKIs erlotinib, gefitinib, and afatinib have been well described, with the EGFR T790M mutation driving resistance in at least half of patients. [7][8][9] The activation of bypass pathways has also been observed as a potential mechanism of resistance to EGFR TKIs, and involves multiple pathways of at least 4 different types of alterations in multiple genes, including focal copy number amplifications in MET, ERBB2 (HER2), or ERBB3; missense mutations in BRAF, MAP2K1 (MEK1), PIK3CA, or KRAS; inactivating mutations or allelic loss in PTEN or RB1 (the latter a hallmark of epithelial-mesenchymal transition to a small-cell phenotype), and fusions in ALK. [7][8][9] The third-generation EGFR TKIs osimertinib and rociletinib inhibit both EGFR activating and T790M mutations, and have demonstrated activity in NSCLC patients with disease that progressed while receiving therapy with firstor second-generation EGFR inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Cell-Free DNA Next-Generation Sequencing Prediction of Response and Resistance to Third-Generation EGFR Inhibitor

Helman

Nguyen

Karlovich

et al. 2018

Clinical Lung Cancer

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We profiled 77 nonesmall-cell lung cancer patients with paired baseline and progression blood samples treated with the third-generation EGFR tyrosine kinase inhibitor (TKI) rociletinib using a broad cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) gene panel. We demonstrated a utility of cfDNA NGS to detect EGFR T790M and predict response comparable to tissue-based tests, even at low allele fractions, and we identified resistance mechanisms. Our findings highlight the genomic heterogeneity observed in disease after progression while receiving therapy with a third-generation EGFR TKI. Introduction: The genomic alterations driving resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) are not well established, and collecting tissue biopsy samples poses potential complications from invasive procedures. Cell-free circulating DNA (cfDNA) testing provides a noninvasive approach to identify potentially targetable mechanisms of resistance. Here we utilized a 70-gene cfDNA next-generation sequencing test to interrogate pretreatment and progression samples from 77 EGFR-mutated non-small cell lung cancer (NSCLC) patients treated with a third-generation EGFR TKI. Patients and Methods: Rociletinib was evaluated in advanced or metastatic (second line or higher) disease with EGFR T790M-positive NSCLC in the TIGER-X (NCT01526928) and TIGER-2 (NCT02147990) studies. Plasma samples were collected at baseline and at the time of systemic progression while receiving rociletinib. The critical exons in 70 genes were sequenced in cfDNA isolated from plasma samples to elucidate a comprehensive genomic profile of alterations for each patient. Results: Plasma-based cfDNA analysis identified 93% of the initial EGFR activating and 85% of the EGFR T790M resistance mutations in pretreatment samples with detectable tumor DNA. Profiling of progression samples revealed significant heterogeneity, with different variant types (eg, mutations, amplifications, and fusions) detected in multiple genes (EGFR, MET, RB1) that may be driving resistance in patients. Novel alterations not previously described in association with resistance to third-generation TKIs were also detected, such as an NTRK1 fusion. Conclusion: cfDNA next-generation sequencing identified initial EGFR activating and secondary T790M resistance mutations in NSCLC patients with high sensitivity, predicted treatment response equivalent to tissue analysis, and identified multiple novel and established resistance alterations.

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Drug Resistance to EGFR Inhibitors in Lung Cancer

Cited by 63 publications

References 129 publications

Hypoxia Induces Multidrug Resistance via Enhancement of Epidermal Growth Factor-Like Domain 7 Expression in Non-Small Lung Cancer Cells

Hypoxia Induces Multidrug Resistance via Enhancement of Epidermal Growth Factor-Like Domain 7 Expression in Non-Small Lung Cancer Cells

Clinical Efficacy of Afatinib Treatment for a Patient with Leptomeningeal Carcinomatosis

Cell-Free DNA Next-Generation Sequencing Prediction of Response and Resistance to Third-Generation EGFR Inhibitor

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