Activation of the AXL Kinase Causes Resistance to EGFR-Targeted Therapy in Lung Cancer

1] Department of Pathology, Case Western Reserve University School of Medicine, University Hospitals-Case Medical Center and Ireland Cancer Center, Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
Nature Genetics (Impact Factor: 29.35). 07/2012; 44(8):852-60. DOI: 10.1038/ng.2330
Source: PubMed


Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.

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    • "Axl oncogenic signalling promotes cancer cell survival, proliferation, migration, and invasion (Han et al, 2013). It is recently reported that activation of Axl is required for erlotinib resistance in epidermal growth factor receptor (EGFR)-mutant non-small-cell lung carcinoma (NSCLC) tumour (Zhang et al, 2012), and thus targeting Axl may prevent or overcome acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in individuals with EGFR-mutant lung cancer. The signals downstream of Axl are mitogen-activated protein kinases (MAPKs)/extracellular signal regulated kinases (ERKs) or phosphatidylinositol 3 kinase (PI3K)/Akt pathway depending on cancer type (Melaragno et al, 1999; Collett et al, 2007). "
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    ABSTRACT: Axl plays multiple roles in tumourigenesis in several cancers. Here we evaluated the expression and biological function of Axl in renal cell carcinoma (RCC). Axl expression was analysed in a tissue microarray of 174 RCC samples by immunostaining and a panel of 11 normal tumour pairs of human RCC tissues by western blot, as well as in RCC cell lines by both western blot and quantitative PCR. The effects of Axl knockdown in RCC cells on cell growth and signalling were investigated. The efficacy of a humanised Axl targeting monoclonal antibody hMAb173 was tested in histoculture and tumour xenograft. We have determined by immunohistochemistry (IHC) that Axl is expressed in 59% of RCC array samples with moderate to high in 20% but not expressed in normal kidney tissue. Western blot analysis of 11 pairs of tumour and adjacent normal tissue show high Axl expression in 73% of the tumours but not normal tissue. Axl is also expressed in RCC cell lines in which Axl knockdown reduces cell viability and PI3K/Akt signalling. The Axl antibody hMAb173 significantly induced RCC cell apoptosis in histoculture and inhibited the growth of RCC tumour in vivo by 78%. The hMAb173-treated tumours also had significantly reduced Axl protein levels, inhibited PI3K signalling, decreased proliferation, and induced apoptosis. Axl is highly expressed in RCC and critical for RCC cell survival. Targeting Axl is a potential approach for RCC treatment.British Journal of Cancer advance online publication, 16 July 2015; doi:10.1038/bjc.2015.237
    British Journal of Cancer 07/2015; 113(4). DOI:10.1038/bjc.2015.237 · 4.84 Impact Factor
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    • "Several phase II clinical trials with foretinib are in progress, addressing breast, liver, renal, gastric, and other cancers (Choueiri et al., 2013; Liu et al., 2009; Shah et al., 2013). Zhang et al. (2012) recently identified that activation of the AXL kinase is a mechanism by which resistance is acquired to EGFR-targeted tyrosine kinase inhibitors (TKIs) in EGFR mutant non-small-cell lung cancers. In some cases, they found that AXL upregulation occurs in the context of what appeared to be epithelial to MES transition (EMT) and EMT-associated transcriptional reprogramming, leading to acquired resistance. "
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    ABSTRACT: Glioblastoma is a highly lethal cancer for which novel therapeutics are urgently needed. Two distinct subtypes of glioblastoma stem-like cells (GSCs) were recently identified: mesenchymal (MES) and proneural (PN). To identify mechanisms to target the more aggressive MES GSCs, we combined transcriptomic expression analysis and kinome-wide short hairpin RNA screening of MES and PN GSCs. In comparison to PN GSCs, we found significant upregulation and phosphorylation of the receptor tyrosine kinase AXL in MES GSCs. Knockdown of AXL significantly decreased MES GSC self-renewal capacity in vitro and inhibited the growth of glioblastoma patient-derived xenografts. Moreover, inhibition of AXL with shRNA or pharmacologic inhibitors also increased cell death significantly more in MES GSCs. Clinically, AXL expression was elevated in the MES GBM subtype and significantly correlated with poor prognosis in multiple cancers. In conclusion, we identified AXL as a potential molecular target for novel approaches to treat glioblastoma and other solid cancers. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 04/2015; 24(5). DOI:10.1016/j.stemcr.2015.03.005 · 5.37 Impact Factor
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    • "In addition, our findings point out that Axl expression is higher in advanced stages of the disease. In fact, Axl has been linked to poor prognosis and resistance to cancer therapy in several tumor types (Zhang et al., 2012). Interestingly, Axl has been shown to play an important role for adenocarcinomatous esophageal cancer (Hector et al., 2010; Hong et al., 2013); however, its role in the malignancy of OSCC has remained unknown up to now. "
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    ABSTRACT: The receptor tyrosine kinase Axl has been described as an oncogene and its deregulation has been implicated in the progression of several human cancers. While the role of Axl in oesophageal adenocarcinoma has been addressed, there is no information about its role in oesophageal squamous cell carcinoma. In the current report, we identified, for the first time, deregulation of Axl expression in oesophageal squamous cell carcinoma (OSCC). Axl is consistently overexpressed in OSCC cell lines and human tumor samples, mainly in advanced stages of the disease. Blockage of Axl gene expression by small interfering RNA inhibits cell survival, proliferation, migration, and invasion in vitro and oesophageal tumor growth in vivo. Additionally, repression of Axl expression results in Akt-dependent inhibition of pivotal genes involved in the NF-κB pathway and in the induction of GSK3β activity, resulting in loss of mesenchymal and induction of epithelial markers. Furthermore, treatment of oesophageal cancer cells with the Akt inhibitor wortmannin inhibits NF-κB signaling, induces GSK3β activity and blocks OSCC cell proliferation in an Axl-dependent manner. Taken together, our results establish a clear role for Axl in OSCC tumorigenesis with potential therapeutic implications. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 01/2015; DOI:10.1091/mbc.E14-04-0868 · 4.47 Impact Factor
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