ECB-ART-50024
Acta Pharm Sin B
2015 Sep 01;55:390-401. doi: 10.1016/j.apsb.2015.07.001.
Show Gene links
Show Anatomy links
Mechanisms of resistance to EGFR tyrosine kinase inhibitors.
Huang L
,
Fu L
.
Abstract
Since the discovery that non-small cell lung cancer (NSCLC) is driven by epidermal growth factor receptor (EGFR) mutations, the EGFR tyrosine kinase inhibitors (EGFR-TKIs, e.g., gefitinib and elrotinib) have been effectively used for clinical treatment. However, patients eventually develop drug resistance. Resistance to EGFR-TKIs is inevitable due to various mechanisms, such as the secondary mutation (T790M), activation of alternative pathways (c-Met, HGF, AXL), aberrance of the downstream pathways (K-RAS mutations, loss of PTEN), impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism), histologic transformation, ATP binding cassette (ABC) transporter effusion, etc. Here we review and summarize the known resistant mechanisms to EGFR-TKIs and provide potential targets for development of new therapeutic strategies.
PubMed ID: 26579470
PMC ID: PMC4629442
Article link: Acta Pharm Sin B
Article Images: [+] show captions
References [+] :
Akhavan,
De-repression of PDGFRβ transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients.
2013, Pubmed
Akhavan, De-repression of PDGFRβ transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients. 2013, Pubmed
Alam, Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinib-responsive adenocarcinoma of the lung. 2010, Pubmed
Azuma, FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor. 2014, Pubmed
Bae, Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer. 2013, Pubmed
Ballas, Rationale for targeting VEGF, FGF, and PDGF for the treatment of NSCLC. 2011, Pubmed
Bean, Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. 2008, Pubmed
Bethune, Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. 2010, Pubmed
Bianco, Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells. 2008, Pubmed
Bidkhori, Modeling of tumor progression in NSCLC and intrinsic resistance to TKI in loss of PTEN expression. 2012, Pubmed
Bonavia, EGFRvIII promotes glioma angiogenesis and growth through the NF-κB, interleukin-8 pathway. 2012, Pubmed
Brown, Integrin-mediated resistance to epidermal growth factor receptor-targeted therapy: an inflammatory situation. 2014, Pubmed
Capaccione, Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma. 2014, Pubmed
Chatterjee, Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. 2013, Pubmed
Cheung, Amplification of CRKL induces transformation and epidermal growth factor receptor inhibitor resistance in human non-small cell lung cancers. 2011, Pubmed
Ciardiello, EGFR antagonists in cancer treatment. 2008, Pubmed
Costa, BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. 2007, Pubmed
Cross, AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. 2014, Pubmed
de Bruin, Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. 2014, Pubmed
de Mello, Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies. 2011, Pubmed
Engelman, MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. 2007, Pubmed
Engelman, PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. 2007, Pubmed
Fujita, Highly sensitive detection of EGFR T790M mutation using colony hybridization predicts favorable prognosis of patients with lung cancer harboring activating EGFR mutation. 2012, Pubmed
Graves, The tumor microenvironment in non-small-cell lung cancer. 2010, Pubmed
Guix, Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. 2008, Pubmed
Hoeflich, Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. 2012, Pubmed
Hofmann, K-RAS mutant pancreatic tumors show higher sensitivity to MEK than to PI3K inhibition in vivo. 2012, Pubmed
Hong, Luteolin is effective in the non-small cell lung cancer model with L858R/T790M EGF receptor mutation and erlotinib resistance. 2014, Pubmed
Hong, Hsp90 inhibition by WK88-1 potently suppresses the growth of gefitinib-resistant H1975 cells harboring the T790M mutation in EGFR. 2014, Pubmed
Huang, β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. 2011, Pubmed
Ishiguro, Epidermal growth factor receptor tyrosine kinase inhibition up-regulates interleukin-6 in cancer cells and induces subsequent development of interstitial pneumonia. 2013, Pubmed
Jameson, Activation of the insulin-like growth factor-1 receptor alters p27 regulation by the epidermal growth factor receptor in oral squamous carcinoma cells. 2013, Pubmed
Ju, Integrin beta1 over-expression associates with resistance to tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. 2010, Pubmed
Ju, Association of integrin beta1 and c-MET in mediating EGFR TKI gefitinib resistance in non-small cell lung cancer. 2013, Pubmed
Kanda, Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. 2013, Pubmed
Katanasaka, Epidermal growth factor receptor variant type III markedly accelerates angiogenesis and tumor growth via inducing c-myc mediated angiopoietin-like 4 expression in malignant glioma. 2013, Pubmed
Khan, A novel insertion mutation on exon 20 of epidermal growth factor receptor, conferring resistance to erlotinib. 2014, Pubmed
Kim, mTOR inhibitors radiosensitize PTEN-deficient non-small-cell lung cancer cells harboring an EGFR activating mutation by inducing autophagy. 2013, Pubmed
Kim, Glycolysis inhibition sensitizes non-small cell lung cancer with T790M mutation to irreversible EGFR inhibitors via translational suppression of Mcl-1 by AMPK activation. 2013, Pubmed
Kim, Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation. 2012, Pubmed
Kiyota, FTY720 induces apoptosis of chronic myelogenous leukemia cells via dual activation of BIM and BID and overcomes various types of resistance to tyrosine kinase inhibitors. 2013, Pubmed
Kobayashi, EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. 2005, Pubmed
Kubo, MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors. 2009, Pubmed
Kwak, Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. 2010, Pubmed
Landi, HER2 and lung cancer. 2013, Pubmed
Lee, Gas6 induces cancer cell migration and epithelial-mesenchymal transition through upregulation of MAPK and Slug. 2013, Pubmed
Lin, CRKL promotes lung cancer cell invasion through ERK-MMP9 pathway. 2015, Pubmed
Ma, T790M and acquired resistance of EGFR TKI: a literature review of clinical reports. 2011, Pubmed
Mueller, Fibroblast-secreted hepatocyte growth factor mediates epidermal growth factor receptor tyrosine kinase inhibitor resistance in triple-negative breast cancers through paracrine activation of Met. 2012, Pubmed
Nakade, Triple inhibition of EGFR, Met, and VEGF suppresses regrowth of HGF-triggered, erlotinib-resistant lung cancer harboring an EGFR mutation. 2014, Pubmed
Nakata, Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity. 2014, Pubmed
Nanjo, Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors. 2013, Pubmed
Ng, A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. 2012, Pubmed
Nishida, A novel gene-protein assay for evaluating HER2 status in gastric cancer: simultaneous analyses of HER2 protein overexpression and gene amplification reveal intratumoral heterogeneity. 2015, Pubmed
Ohashi, Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. 2012, Pubmed
Palena, Influence of IL-8 on the epithelial-mesenchymal transition and the tumor microenvironment. 2012, Pubmed
Pao, KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. 2005, Pubmed
Park, CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance. 2014, Pubmed
Pearson, Targeted therapy for NSCLC: ALK inhibition. 2012, Pubmed
Peled, Insulin-like growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. 2013, Pubmed
Perez-Torres, Epidermal growth factor receptor (EGFR) antibody down-regulates mutant receptors and inhibits tumors expressing EGFR mutations. 2006, Pubmed
Qu, Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation. 2014, Pubmed
Ren, The PI3 kinase inhibitor NVP-BKM120 induces GSK3/FBXW7-dependent Mcl-1 degradation, contributing to induction of apoptosis and enhancement of TRAIL-induced apoptosis. 2013, Pubmed
Repasky, Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis? 2004, Pubmed
Rho, MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation. 2014, Pubmed
Rutkowski, Dabrafenib for the treatment of BRAF V600-positive melanoma: a safety evaluation. 2014, Pubmed
Sarkar, Targeted therapy against EGFR and VEGFR using ZD6474 enhances the therapeutic potential of UV-B phototherapy in breast cancer cells. 2013, Pubmed
Sasaki, A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. 2011, Pubmed
Schoeberl, An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. 2010, Pubmed
Shi, Sildenafil reverses ABCB1- and ABCG2-mediated chemotherapeutic drug resistance. 2011, Pubmed
Smith, The HSP90 inhibitor ganetespib potentiates the antitumor activity of EGFR tyrosine kinase inhibition in mutant and wild-type non-small cell lung cancer. 2015, Pubmed
Soda, Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. 2007, Pubmed , Echinobase
Sodani, GW583340 and GW2974, human EGFR and HER-2 inhibitors, reverse ABCG2- and ABCB1-mediated drug resistance. 2012, Pubmed
Song, Antitumor efficacy of the anti-interleukin-6 (IL-6) antibody siltuximab in mouse xenograft models of lung cancer. 2014, Pubmed
Sos, PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. 2009, Pubmed
Su, Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. 2012, Pubmed
Suda, CRKL amplification is rare as a mechanism for acquired resistance to kinase inhibitors in lung cancers with epidermal growth factor receptor mutation. 2014, Pubmed
Suda, EGFR T790M mutation: a double role in lung cancer cell survival? 2009, Pubmed
Thiery, Epithelial-mesenchymal transitions in tumour progression. 2002, Pubmed
Toyooka, The epidermal growth factor receptor D761Y mutation and effect of tyrosine kinase inhibitor. 2007, Pubmed
Walter, Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. 2013, Pubmed
Wang, STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. 2013, Pubmed
Wang, PIK3CA mutations frequently coexist with EGFR/KRAS mutations in non-small cell lung cancer and suggest poor prognosis in EGFR/KRAS wildtype subgroup. 2014, Pubmed
Ware, Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. 2010, Pubmed
Whyte, Correlation of PIK3Ca mutations with gene expression and drug sensitivity in NCI-60 cell lines. 2006, Pubmed
Wilson, Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition. 2014, Pubmed
Woo, Epidermal growth factor receptor (EGFR) exon 20 mutations in non-small-cell lung cancer and resistance to EGFR-tyrosine kinase inhibitors. 2014, Pubmed
Xia, An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models. 2013, Pubmed
Xie, Notch-1 contributes to epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance in non-small cell lung cancer in vitro and in vivo. 2013, Pubmed
Xu, Low expression of the FoxO4 gene may contribute to the phenomenon of EMT in non-small cell lung cancer. 2014, Pubmed
Yamada, Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells. 2012, Pubmed
Yano, Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. 2008, Pubmed
Yao, TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. 2010, Pubmed
Yu, Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. 2013, Pubmed
Yun, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. 2008, Pubmed
Zhang, Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. 2012, Pubmed
Zhang, Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. 2010, Pubmed