Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib

Xu, Yan; Liu, Hongyu; Chen, Jun; Zhou, Qinghua

doi:10.4161/cbt.9.8.11881

Cited by 63 publications

(51 citation statements)

References 72 publications

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“…Resistance to reversible HER1 TKIs such as gefitinib has increased, leading to the development of novel target-based therapies such as dacomitinib for the treatment of NSCLC harbouring exon 19 deletions or exon 21 (L858R) mutations [35][36][37]. Conventional HER TKIs such as gefitinib are reversible: they competitively bind to the HER1 tyrosine kinase domain [38].…”

Section: Second-generation Human Epidermal Growth Factor Receptor Tyrmentioning

confidence: 99%

Gastrointestinal toxicities of first and second-generation small molecule human epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer

Sebille

Gibson²,

Wardill³

et al. 2016

Current Opinion in Supportive &Amp; Palliative Care

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Section: Second-generation Human Epidermal Growth Factor Receptor Tyrmentioning

confidence: 99%

Gastrointestinal toxicities of first and second-generation small molecule human epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer

Sebille

Gibson²,

Wardill³

et al. 2016

Current Opinion in Supportive &Amp; Palliative Care

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“…Primary and acquired (secondary) resistance to erlotinib can occur through several distinct molecular mechanisms, [11][12][13][14][15][16][17] including the emergence of malignant clones containing second-site mutations in the EGFR kinase domain that abrogate the inhibitory activity of EGFR TKI (e.g., the so-called "gatekeeper mutation", which involves a substitution of methionine for threonine at position 790 [T790M]). Other molecular mechanisms include the acquisition of activating mutations downstream of EGFR (e.g., K-Ras or PI3K ), amplification of the MET receptor tyrosine kinase (RTK) gene, or loss of the tumor suppressor gene PTEN.…”

Section: Introductionmentioning

confidence: 99%

Stem cell-like ALDH^brightcellular states in EGFR-mutant non-small cell lung cancer: A novel mechanism of acquired resistance to erlotinib targetable with the natural polyphenol silibinin

et al. 2013

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The enrichment of cancer stem cell (CSC)-like cellular states has not previously been considered to be a causative mechanism in the generalized progression of EGFR-mutant non-small cell lung carcinomas (NSCLC) after an initial response to the EGFR tyrosine kinase inhibitor erlotinib. To explore this possibility, we utilized a pre-clinical model of acquired erlotinib resistance established by growing NSCLC cells containing a TKI-sensitizing EGFR exon 19 deletion (ΔE746-A750) in the continuous presence of high doses of erlotinib. Genome-wide analyses using Agilent 44K Whole Human Genome Arrays were evaluated via bioinformatics analyses through GSEA-based screening of the KEGG pathway database to identify the molecular circuitries that were over-represented in the transcriptomic signatures of erlotinib-refractory cells. The genomic spaces related to erlotinib resistance included a preponderance of cell cycle genes (E2F1, - 2, CDC2, -6) and DNA replication-related genes (MCM4, - 5, - 6, - 7), most of which are associated with early lung development and poor prognosis. In addition, metabolic genes such as ALDH1A3 (a candidate marker for lung cancer cells with CSC-like properties) were identified. Thus, we measured the proportion of erlotinib-resistant cells expressing very high levels of aldehyde dehydrogenase (ALDH) activity attributed to ALDH1/3 isoforms. Using flow cytometry and the ALDEFLUOR® reagent, we confirmed that erlotinib-refractory cell populations contained drastically higher percentages (> 4500%) of ALDH(bright) cells than the parental erlotinib-responsive cells. Notably, strong decreases in the percentages of ALDH(bright) cells were observed following incubation with silibinin, a bioactive flavonolignan that can circumvent erlotinib resistance in vivo. The number of lung cancer spheres was drastically suppressed by silibinin in a dose-dependent manner, thus confirming the ability of this agent to inhibit the self-renewal of erlotinib-refractory CSC-like cells. This report is the first to show that: (1) loss of responsiveness to erlotinib in EGFR-mutant NSCLC can be explained in terms of erlotinib-refractory ALDH(bright) cells, which have been shown to exhibit stem cell-like properties; and (2) erlotinib-refractory ALDH(bright) cells are sensitive to the natural agent silibinin. Our findings highlight the benefit of administration of silibinin in combination with EGFR TKIs to target CSCs and minimize the ability of tumor cells to escape cell death in EGFR-mutant NSCLC patients.

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“…The acquisition of resistance to EGFR TKIs has been attributed to two main mechanisms reviewed in 6789101112. The first is the emergence of malignant clones containing second-site mutations in the EGFR kinase domain that abrogate the inhibitory activity of EGFR TKIs.…”

mentioning

confidence: 99%

Silibinin suppresses EMT-driven erlotinib resistance by reversing the high miR-21/low miR-200c signature in vivo

Cufí

Bonavia

Vázquez-Martín

et al. 2013

Sci Rep

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The flavolignan silibinin was studied for its ability to restore drug sensitivity to EGFR-mutant NSCLC xenografts with epithelial-to-mesenchymal transition (EMT)-driven resistance to erlotinib. As a single agent, silibinin significantly decreased the tumor volumes of erlotinib-refractory NSCLC xenografts by approximately 50%. Furthermore, the complete abrogation of tumor growth was observed with the co-treatment of erlotinib and silibinin. Silibinin fully reversed the EMT-related high miR-21/low miR-200c microRNA signature and repressed the mesenchymal markers SNAIL, ZEB, and N-cadherin observed in erlotinib-refractory tumors. Silibinin was sufficient to fully activate a reciprocal mesenchymal-to-epithelial transition (MET) in erlotinib-refractory cells and prevent the highly migratogenic phenotype of erlotinib-resistant NSCLC cells. Given that the various mechanisms of resistance to erlotinib result from EMT, regardless of the EGFR mutation status, a water-soluble, silibinin-rich milk thistle extract might be a suitable candidate therapy for upcoming clinical trials aimed at preventing or reversing NSCLC progression following erlotinib treatment.

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Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib

Cited by 63 publications

References 72 publications

Gastrointestinal toxicities of first and second-generation small molecule human epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer

Gastrointestinal toxicities of first and second-generation small molecule human epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer

Stem cell-like ALDH^brightcellular states in EGFR-mutant non-small cell lung cancer: A novel mechanism of acquired resistance to erlotinib targetable with the natural polyphenol silibinin

Silibinin suppresses EMT-driven erlotinib resistance by reversing the high miR-21/low miR-200c signature in vivo

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Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib

Cited by 63 publications

References 72 publications

Gastrointestinal toxicities of first and second-generation small molecule human epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer

Gastrointestinal toxicities of first and second-generation small molecule human epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer

Stem cell-like ALDHbrightcellular states in EGFR-mutant non-small cell lung cancer: A novel mechanism of acquired resistance to erlotinib targetable with the natural polyphenol silibinin

Silibinin suppresses EMT-driven erlotinib resistance by reversing the high miR-21/low miR-200c signature in vivo

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Stem cell-like ALDH^brightcellular states in EGFR-mutant non-small cell lung cancer: A novel mechanism of acquired resistance to erlotinib targetable with the natural polyphenol silibinin