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Review
. 2021 Dec;147(12):3653-3664.
doi: 10.1007/s00432-021-03828-8. Epub 2021 Oct 18.

Drug resistance of targeted therapy for advanced non-small cell lung cancer harbored EGFR mutation: from mechanism analysis to clinical strategy

Yuxin Zhao #  1   2   3 , Haiyong Wang #  1   2   3   4 , Chengwei He  5   6   7
Affiliations
Review

Drug resistance of targeted therapy for advanced non-small cell lung cancer harbored EGFR mutation: from mechanism analysis to clinical strategy

Yuxin Zhao et al. J Cancer Res Clin Oncol. 2021 Dec.

Abstract

Purpose: Non-small cell lung cancer (NSCLC) accounts for about 85% in all cases of lung cancer. In recent years, molecular targeting drugs for NSCLC have been developed rapidly. The epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have changed the paradigm of cancer therapy from empirical cytotoxic chemotherapy to molecular-targeted cancer therapy. Currently, there are three generations of EGFR-TKIs, all of which have achieved good efficacy in clinical therapy. However, most patients developed drug resistance after 6-13 months EGFR-TKIs treatment. Therefore, a comprehensive understanding of EGFR-TKIs resistance mechanisms is of vital importance for clinical management of NSCLC.

Methods: Relevant data and information about the topic were obtained by searching PubMed (Medline), Web of Science and Google Scholar using the subject headings, such as "NSCLC", "EGFR-TKIs resistance", "EGFR mutations", "human epidermal growth factor receptor-2 (HER2/erbB-2)", "hepatocyte growth factor (HGF)", "vascular endothelial growth factor (VEGF)", "insulin-like growth factor 1 (IGF-1)", "epithelial-mesenchymal transition (EMT)", "phosphatase and tensin homolog (PTEN)", "RAS mutation", "BRAF mutation", "signal transducer and activator of transcription 3 (STAT3)", and "tumor microenvironment", etc. RESULTS: The mechanisms for EGFR-TKIs resistance include EGFR mutations, upregulation of HER2, HGF/c-MET, VEGF IGF1, EMT and STAT3 pathways, mutations of PTEN, RAS and BRAF genes, and activation of other by-pass pathways. These mechanisms are interconnected and can be potential targets for the treatment of NSCLC.

Conclusion: In this review, we discuss the mechanisms of EGFR-TKIs drug resistance and the clinical strategies to overcome drug resistance from the perspective of EGFR-TKIs combined treatment.

Keywords: Drug resistance; Epidermal growth factor receptor-tyrosine kinase inhibitor; Non-small cell lung cancer; Targeted therapy.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

Fig. 1
Fig. 1
Targeted resistance mechanisms of epidermal growth factor receptor-inhibitors (EGFR-TKIs)
See this image and copyright information in PMC

References

    1. Apicella M et al (2018) Increased lactate secretion by cancer cells sustains non-cell-autonomous adaptive resistance to MET and EGFR targeted therapies. Cell Metab 28:848−865 - PubMed
    1. Balak MN et al (2006) Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor—mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12:6494–6501 - PubMed
    1. Bean J et al (2008) Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res 14:7519–7525 - PMC - PubMed
    1. Bivona TG et al (2011) FAS and NF-kappa B signalling modulate dependence of lung cancers on mutant EGFR. Nature 471:523–526 - PMC - PubMed
    1. Blakely CM et al (2015) NF-kappa B-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep 11:98–110 - PMC - PubMed

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