Understanding resistance to EGFR inhibitors—Impact on future treatment strategies

Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison, WI 53705, USA.
Nature Reviews Clinical Oncology (Impact Factor: 14.18). 09/2010; 7(9):493-507. DOI: 10.1038/nrclinonc.2010.97
Source: PubMed


EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. Following ligand binding, EGFR stimulates downstream cell signaling cascades that influence cell proliferation, apoptosis, migration, survival and complex processes, including angiogenesis and tumorigenesis. EGFR has been strongly implicated in the biology of human epithelial malignancies, with therapeutic applications in cancers of the colon, head and neck, lung, and pancreas. Accordingly, targeting EGFR has been intensely pursued, with the development of a series of promising molecular inhibitors for use in clinical oncology. As is common in cancer therapy, challenges with respect to treatment resistance emerge over time. This situation is certainly true of EGFR inhibitor therapies, where intrinsic and acquired resistance is now well recognized. In this Review, we provide a brief overview regarding the biology of EGFR, preclinical and clinical development of EGFR inhibitors, and molecular mechanisms that underlie the development of treatment resistance. A greater understanding of the mechanisms that lead to EGFR resistance may provide valuable insights to help design new strategies that will enhance the impact of this promising class of inhibitors for the treatment of cancer.

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Available from: Emily F Dunn, Mar 28, 2014
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    • "Notably, the most influential components are enriched with several already known drug targets. However, many of these drug targets (EGFR, ERK, Ras, PI3K etc.) have been associated with drug resistance (West et al., 2002;Kobayashi et al., 2005;Linardou et al., 2008;Wheeler et al., 2010;Dienstmann et al., 2012). The mechanism of drug resistance includes mutation in the targeted protein or expression of other genes (altered expression) to bypass the effect caused by perturbation, and deregulation in apoptosis, etc. (Gottesman, 2002;Holohan et al., 2013). "
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    ABSTRACT: Dysregulation in signal transduction pathways can lead to a variety of complex disorders, including cancer. Computational approaches such as network analysis are important tools to understand system dynamics as well as to identify critical components that could be further explored as therapeutic targets. Here, we performed perturbation analysis of a large-scale signal transduction model in extracellular environments that stimulate cell death, growth, motility, and quiescence. Each of the model's components was perturbed under both loss-of-function and gain-of-function mutations. We identified the most and least influential components based on the magnitude of their influence on the rest of the system. Based on the premise that the most influential components might serve as better drug targets, we characterized them for biological functions, housekeeping genes, essential genes, and druggable proteins. Moreover, known cancer drug targets were also classified in influential components based on the affected components in the network. Additionally, the systemic perturbation analysis of the model revealed a network motif of most influential components which affect each other. Furthermore, our analysis predicted novel combinations of cancer drug targets with various effects on other most influential components. We found that the combinatorial perturbation consisting of PI3K inactivation and overactivation of IP3R1 can lead to increased activity levels of apoptosis-related components and tumor suppressor genes, suggesting that this combinatorial perturbation may lead to a better target for decreasing cell proliferation and inducing apoptosis. Lastly, our results suggest that systematic perturbation analyses of large-scale computational models may serve as an approach to prioritize and assess signal transduction components in order to identify novel drug targets in complex disorders.
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    • "The epidermal growth factor receptor (EGFR) is a potent tyrosine kinase, which through downstream signaling networks regulates such basic cell functions as proliferation, chemotactic migration, invasion, and avoidance of apoptosis [1] [2]. Elevated expression and constitutive activity of EGFR have been strongly associated with poor prognosis in many types of cancer, prompting the design of highly specific and potent EGFR inhibitors to control tumor growth and metastasis [3] [4] [5]. Those inhibitors include anti-EGFR monoclonal antibodies (mAbs) directed against the extracellular domain of the EGFR and small molecule tyrosine kinase inhibitors directed against the catalytic domain of the EGFR [6] [7]. "
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    ABSTRACT: Many malignant characteristics of cancer cells are regulated through pathways induced by the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Herein, we show that besides directly affecting the biology of cancer cells per se, EGFR also regulates the primary tumor microenvironment. Specifically, our findings demonstrate that both the expression and signaling activity of EGFR are required for the induction of a distinct intratumoral vasculature capable of sustaining tumor cell intravasation, a critical rate-limiting step in the metastatic cascade. An intravasation-sustaining mode of intratumoral angiogenic vessels depends on high levels of tumor cell EGFR and the interplay between EGFR-regulated production of interleukin 8 by tumor cells, interleukin-8–induced influx of tumor-infiltrating neutrophils delivering their unique matrix metalloproteinase-9, and neutrophil matrix metalloproteinase-9–dependent release of the vascular permeability and endothelial growth factor, VEGF. Our data indicate that through VEGF-mediated disruption of endothelial layer integrity and increase of intratumoral vasculature permeability, EGFR activity significantly facilitates active intravasation of cancer cells. Therefore, this study unraveled an important but overlooked function of EGFR in cancer, namely, its ability to create an intravasation-sustaining microenvironment within the developing primary tumor by orchestrating several interrelated processes required for the initial steps of cancer metastasis through vascular routes. Our findings also suggest that EGFR-targeted therapies might be more effective when implemented in cancer patients with early-staged primary tumors containing a VEGF-dependent angiogenic vasculature. Accordingly, early EGFR inhibition combined with various anti-VEGF approaches could synergistically suppress tumor cell intravasation through inhibiting the highly permeable angiogenic vasculature induced by EGFR-overexpressing aggressive cancer cells.
    Neoplasia (New York, N.Y.) 08/2015; 17(8):634-649. DOI:10.1016/j.neo.2015.08.002 · 4.25 Impact Factor
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    • "Moreover, activation of Akt/mTOR survival pathway is also observed in patients with acquired resistance [41]. IGF-1R (insulin-like growth factor) that is ubiquitously expressed on cancer cell surface is also implicated in mediating resistance to EGFR inhibitor therapies [41]. In all the cases, alternate signaling pathways were found to adapt the tumors to flourish even in the presence of the targeted agents. "
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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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