Mechanisms of Resistance to Epidermal Growth Factor Receptor Inhibitors and Novel Therapeutic Strategies to Overcome Resistance in NSCLC Patients

Division of Hematology/Oncology, Department of Medicine, USCF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Chemotherapy research and practice 08/2012; 2012(6):817297. DOI: 10.1155/2012/817297
Source: PubMed


The epidermal growth factor receptor (EGFR) is a well-characterized oncogene that is frequently activated by somatic kinase domain mutations in non-small cell lung cancer (NSCLC). EGFR TKIs are effective therapies for NSCLC patients whose tumors harbor an EGFR activating mutation. However, EGFR TKI treatment is not curative in patients because of both primary and secondary treatment resistance. Studies over the last decade have identified mechanisms that drive primary and secondary resistance to EGFR TKI treatment. The elucidation of mechanisms of resistance to EGFR TKI treatment provides a basis for the development of therapeutic strategies to overcome resistance and enhance outcomes in NSCLC patients. In this paper, we summarize the mechanisms of resistance to EGFR TKIs that have been identified to date and discusses potential therapeutic strategies to overcome EGFR TKI resistance in NSCLC patients.

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Available from: Luping Lin, Jun 23, 2015
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    • "Indeed, the escape from drug sensitivity is one of the major hurdles facing the use of targeted therapeutic agents. A significant amount of work has been done to elucidate the molecular and biological mechanisms involved in drug resistance to various targeted agents, especially the resistance to EGFR inhibitors in the case of NSCLC [41] [42]. The biopsies from NSCLC patients who acquire resistance show that, in addition to the original activating EGFR mutation, other mutations arose like EGFR T790M mutation that interferes with the binding of the drugs like gefitinib or erlotinib to the receptor, amplification of MET tyrosine kinase receptor driving cell growth [43]. "
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    ABSTRACT: Non-small cell lung cancer (NSCLC) patients have very low survival rates because the current therapeutic strategies are not fully effective. Although EGFR tyrosine kinase inhibitors are effective for NSCLC patients harboring EGFR mutations, patients invariably develop resistance to these agents. Alterations in multiple signaling cascades have been associated with the development of resistance to EGFR inhibitors. Sonic Hedgehog and associated Gli transcription factors play a major role in embryonic development and have recently been found to be reactivated in NSCLC, and elevated Gli1 levels correlate with poor prognosis. The Hedgehog pathway has been implicated in the functions of cancer stem cells, although the underlying molecular mechanisms are not clear. In this context, we demonstrate that Gli1 is a strong regulator of embryonic stem cell transcription factor Sox2. Depletion of Gli1 or inhibition of the Hedgehog signaling significantly abrogated the self-renewal of stem-like side-population cells from NSCLCs as well as vascular mimicry of such cells. Gli1 was found to transcriptionally regulate Sox2 through its promoter region, and Gli1 could be detected on the Sox2 promoter. Inhibition of Hedgehog signaling appeared to work cooperatively with EGFR inhibitors in markedly reducing the viability of NSCLC cells as well as the self-renewal of stem-like cells. Thus, our study demonstrates a cooperative functioning of the EGFR signaling and Hedgehog pathways in governing the stem-like functions of NSCLC cancer stem cells and presents a novel therapeutic strategy to combat NSCLC harboring EGFR mutations. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neoplasia 07/2015; 17(7). DOI:10.1016/j.neo.2015.07.001 · 4.25 Impact Factor
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    • "This may in part explain the activity of the afatinib/cetuximab combination (see below). Besides second site mutations and HER reprogramming, several other mechanisms of secondary resistance to reversible EGFR-TKI have been described in the literature (Chen 2012; Hammerman et al. 2009; Kanda et al. 2013; Lin and Bivona 2012; Sequist et al. 2011). These include (1) MET receptor amplifications (Nanjo et al. 2012), (2) PI3K CA mutations, (3) EMT (epithelial mesenchymal transformation) (Hsu et al. 2012), (4) histological SCLC transformation, (5) activation of AXL, (6) activation of IGF1R-signalling, (7) loss of PTEN and enhanced expression (Sos et al. 2009) and activation of (8) integrinβ1 (Kanda et al. 2013) and (9) SRC (Kanda et al. 2013). "
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    ABSTRACT: Afatinib (also known as BIBW 2992) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto- and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members. Afatinib inhibits cellular growth and induces apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network. This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers. Afatinib retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible EGFR inhibitors, such as those exhibiting the T790M mutations. Several combination treatments have been explored to prevent and/or overcome development of resistance to afatinib, the most promising being those with EGFR- or HER2-targeted antibodies, other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules.
    Archiv für Experimentelle Pathologie und Pharmakologie 03/2014; 387(6). DOI:10.1007/s00210-014-0967-3 · 2.47 Impact Factor
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    • "The purpose of this study was to report cases of EGFR-TKI-naïve patients carrying the EGFR mutation, L747S, which is associated with acquired resistance to the drug. Previous studies have revealed that acquired resistance mutations, including L747S, are rare (8,9). There have also been few reports of L747S detection in lung carcinoma patients who have not yet received treatment (11,12). "
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    ABSTRACT: The purpose of the present study was to report cases of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-naïve patients carrying a mutation associated with acquired resistance to the drug. Gene alterations in 77 lung carcinoma patients were analyzed by collecting and studying curette lavage fluid at the time of diagnosis. PCRs were performed to amplify mutation hotspot regions in EGFR genes. The PCR products were direct-sequenced and the mutations confirmed by resequencing using different primers. Case 1 was a 78-year-old Japanese male diagnosed with stage IB lung adenocarcinoma who was found to have two EGFR mutations, G719S and L747S. Case 2 was a 73-year-old Japanese male diagnosed with stage IV squamous cell lung carcinoma and bone metastasis who had the EGFR mutation, L747S. Case 3 was an 82-year-old Japanese male diagnosed with hyponatremia due to inappropriate secretion of antidiuretic hormone and stage IIIB small cell lung carcinoma (SCLC) who had the EGFR mutation, L747S. Thus, the EGFR mutation L747S associated with acquired EGFR-TKI resistance was detected in two non-small cell lung carcinoma (NSCLC) patients and one SCLC patient, none of whom had ever received EGFR-TKI. The patients were current smokers with stages at diagnosis ranging from IB to IV, and their initial tumors contained resistant clones carrying L747S. L747S may be associated with primary resistance. To the best of our knowledge, this study is the first report of an EGFR mutation associated with resistance to EGFR-TKI in SCLC patients. The early detection of EGFR-TKI resistance mutations may be beneficial in making treatment decisions for lung carcinoma patients, including those with SCLC.
    Oncology letters 02/2014; 7(2):357-360. DOI:10.3892/ol.2013.1705 · 1.55 Impact Factor
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