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      Expression, regulation and targeting of receptor tyrosine kinases in esophageal squamous cell carcinoma

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          Abstract

          Esophageal cancer is one of the most common types of cancer, which is a leading cause of cancer-related death worldwide. Based on histological behavior, it is mainly of two types (i) Esophageal squamous cell carcinoma (ESCC), and (ii) esophageal adenocarcinoma (EAD or EAC). In astronomically immense majority of malignancies, receptor tyrosine kinases (RTKs) have been kenned to play a consequential role in cellular proliferation, migration, and metastasis of the cells. The post-translational modifications (PTMs) including phosphorylation of tyrosine (pY) residue of the tyrosine kinase (TK) domain have been exploited for treatment in different malignancies. Lung cancer where pY residues of EGFR have been exploited for treatment purpose in lung adenocarcinoma patients, but we do not have such kind of felicitously studied and catalogued data in ESCC patients. Thus, the goal of this review is to summarize the studies carried out on ESCC to explore the role of RTKs, tyrosine kinase inhibitors, and their pertinence and consequentiality for the treatment of ESCC patients.

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          Genetic landscape of esophageal squamous cell carcinoma.

          Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.
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            Genomic and molecular characterization of esophageal squamous cell carcinoma

            Esophageal squamous cell carcinoma (ESCC) is a world-wide prevalent cancer, which is particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified novel significantly mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to previously discovered ones (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Moreover, our approaches uncovered many novel druggable candidates, and XPO1 was further explored as a therapeutic target because of its mutation and protein overexpression. Together, our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets.
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              Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.

              Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non-small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 95% CI 0.8-3.1%). Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET.
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                Author and article information

                Contributors
                manoj@theglocaluniversity.in , manojkkashyap@gmail.com
                Omar.abdelrhman@med.asu.edu.eg
                Journal
                Mol Cancer
                Mol. Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                19 February 2018
                19 February 2018
                2018
                : 17
                : 54
                Affiliations
                [1 ]GRID grid.449790.7, School of Life and Allied Health Sciences, , Glocal University, ; Saharanpur, UP 247121 India
                [2 ]GRID grid.430140.2, Department of Applied Sciences and Biotechnology, , Shoolini University of Biotechnology and Management Sciences, ; Solan, Himachal Pradesh India
                [3 ]ISNI 0000 0004 0621 1570, GRID grid.7269.a, Clinical Oncology Department, Faculty of Medicine, , Ain Shams University, ; Cairo, Egypt
                Article
                790
                10.1186/s12943-018-0790-4
                5817798
                29455652
                784ca521-6baf-4643-a16a-5eda668a1e0d
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 16 October 2017
                : 1 February 2018
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                esophageal adenocarcinoma,esophageal squamous cell carcinoma,tyrosine kinase receptor,kinase activity,egfr,vegfr,axl,ptk7,c-met,alk,and pdgfr

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