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      Combination therapy of apatinib with icotinib for primary acquired icotinib resistance in patients with advanced pulmonary adenocarcinoma with EGFR mutation

      case-report

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          Abstract

          Multi‐targeted agents represent the next generation of targeted therapies for solid tumors, and patients with acquired resistance to EGFR‐tyrosine kinase inhibitors (TKIs) may also benefit from their combination with TKI therapy. Third‐generation targeted drugs, such as osimertinib, are very expensive, thus a more economical solution is required. The aim of this study was to explore the use of apatinib combined with icotinib therapy for primary acquired resistance to icotinib in three patients with advanced pulmonary adenocarcinoma with EGFR mutations. We achieved favorable oncologic outcomes in all three patients, with progression‐free survival of four to six months. Unfortunately, the patients ultimately had to cease combination therapy because of intolerable adverse effects of hand and foot syndrome and oral ulcers. Combination therapy of apatinib with icotinib for primary acquired resistance to icotinib may be an option for patients with advanced pulmonary adenocarcinoma with EGFR mutations, but physicians must also be aware of the side effects caused by such therapy.

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          Most cited references20

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          The epidermal growth factor receptor family: biology driving targeted therapeutics.

          The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy.
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            Novel targets in non-small cell lung cancer: ROS1 and RET fusions.

            The discovery of chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) has stimulated renewed interest in oncogenic fusions as potential therapeutic targets. Recently, genetic alterations in ROS1 and RET were identified in patients with NSCLC. Like ALK, genetic alterations in ROS1 and RET involve chromosomal rearrangements that result in the formation of chimeric fusion kinases capable of oncogenic transformation. Notably, ROS1 and RET rearrangements are rarely found with other genetic alterations, such as EGFR, KRAS, or ALK. This finding suggests that both ROS1 and RET are independent oncogenic drivers that may be viable therapeutic targets. In initial screening studies, ROS1 and RET rearrangements were identified at similar frequencies (approximately 1%-2%), using a variety of genotyping techniques. Importantly, patients with either ROS1 or RET rearrangements appear to have unique clinical and pathologic features that may facilitate identification and enrichment strategies. These features may in turn expedite enrollment in clinical trials evaluating genotype-directed therapies in these rare patient populations. In this review, we summarize the molecular biology, clinical features, detection, and targeting of ROS1 and RET rearrangements in NSCLC.
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              Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance.

              The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) gefitinib and erlotinib benefit some non-small cell lung cancer (NSCLC) patients, but most do not respond (primary resistance) and those who initially respond eventually progress (acquired resistance). EGFR TKI resistance is not completely understood and has been associated with certain EGFR and K-RAS mutations and MET amplification. We hypothesized that dual inhibition of the vascular endothelial growth factor (VEGF) and EGFR pathways may overcome primary and acquired resistance. We investigated the VEGF receptor/EGFR TKI vandetanib, and the combination of bevacizumab and erlotinib in vivo using xenograft models of EGFR TKI sensitivity, primary resistance, and three models of acquired resistance, including models with mutated K-RAS and secondary EGFR T790M mutation. Vandetanib, gefitinib, and erlotinib had similar profiles of in vitro activity and caused sustained tumor regressions in vivo in the sensitive HCC827 model. In all four resistant models, vandetanib and bevacizumab/erlotinib were significantly more effective than erlotinib or gefitinib alone. Erlotinib resistance was associated with a rise in both host and tumor-derived VEGF but not EGFR secondary mutations in the KRAS mutant-bearing A549 xenografts. Dual inhibition reduced tumor endothelial proliferation compared with VEGF or EGFR blockade alone, suggesting that the enhanced activity of dual inhibition is due at least in part to antiendothelial effects. These studies suggest that erlotinib resistance may be associated with a rise in both tumor cell and host stromal VEGF and that combined blockade of the VEGFR and EGFR pathways can abrogate primary or acquired resistance to EGFR TKIs. This approach merits further evaluation in NSCLC patients.
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                Author and article information

                Contributors
                249867563@qq.com
                dr_hujian@zju.edu.cn
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                24 March 2018
                May 2018
                : 9
                : 5 ( doiID: 10.1111/tca.2018.9.issue-5 )
                : 656-661
                Affiliations
                [ 1 ] Department of Thoracic Surgery The First Affiliated Hospital, Zhejiang University School of Medicine Hangzhou China
                Author notes
                [*] [* ] Correspondence

                Jian Hu, Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.

                Tel: +86 571 8723 6847

                Fax: +86 571 8723 6847

                Email: dr_hujian@ 123456zju.edu.cn

                Author information
                http://orcid.org/0000-0002-9494-9828
                Article
                TCA12624
                10.1111/1759-7714.12624
                5928351
                29575765
                90363b5a-fbc5-4ec8-be87-1e0beb98ff26
                © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 09 January 2018
                : 10 February 2018
                : 11 February 2018
                Page count
                Figures: 3, Tables: 1, Pages: 6, Words: 3424
                Funding
                Funded by: The Key Project of Zhejiang Province Science and Technology Plan, China
                Award ID: 2014C03032
                Funded by: The National Key Research and Development Program of China
                Award ID: 2017YFC0113500
                Funded by: Key Project of Zhejiang Province Science, Technology Plan12,China
                Categories
                Case Report
                Case Reports
                Custom metadata
                2.0
                tca12624
                May 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.7.2 mode:remove_FC converted:01.05.2018

                acquired resistance,advanced pulmonary adenocarcinoma,apatinib,icotinib,molecular targeted therapy

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