摘要
间变性淋巴瘤激酶(ALK)是癌症治疗的一个药物靶点。总的来说,人类肿瘤中ALK致癌基因的活化是通过基因重排(例如EML4-ALK, NMP-ALK等)发生的。用于“ALK-重排”肺癌的ALK抑制剂的临床使用显著提高了患者的存活率。至今为止,很多关于人类癌变和药物敏感性关系中的ALK基因重排已被发现。然而,来自癌症基因组 Atlas (TCGA, USA) 的新兴的基因组数据目前揭示了除了肺癌以外的多种癌症类型中常见的 ALK基因突变 (~3.06%)。重要的是,最近的一些研究表明,ALK基因突变,ALK基因重排的独立可致癌。因此,ALK基因突变可能对多种癌症类型的致病和治疗很重要。在这里,我们总结了最新的来自TCGA的 17种人类癌症类型的ALK基因突变频率和突变模式。不像许多其他热点基因突变频率高的致癌基因,ALK基因突变往往跨越整个基因。迄今为止,一些经常发生的突变基因 (G263、R401、R551、 P968 和 E1242)和变异丰富的集群区域已被确定,但其功能影响尚不清楚。我们也对所有的ALK基因突变的人类癌细胞系(来自细胞系百科 (CCLE) 和 NCI-60 板)进行了全面的综述,这可以用作ALK基因突变生物学和药物筛选研究的模型系统。最后,我们总结了在致癌和药物敏感性上ALK基因突变的临床前和临床变现,这或许可提供重要的新治疗策略和推动多种癌症类型中未来ALK基因突变研究。
关键词: 获得性耐药,ALK抑制剂敏感性,ALK基因突变,致癌基因的活化。
图形摘要
Current Cancer Drug Targets
Title:A Pan-Cancer Review of ALK Mutations: Implications for Carcinogenesis and Therapy
Volume: 15 Issue: 4
Author(s): Nick Ka Ming Yau, Andrew Yuon Fong, Hiu Fung Leung, Krista Roberta Verhoeft and Qin Ying Lim, Wai Yip Lam, Ian Chi Kei Wong and Vivian Wai Yan Lui
Affiliation:
关键词: 获得性耐药,ALK抑制剂敏感性,ALK基因突变,致癌基因的活化。
摘要: The anaplastic lymphoma kinase (ALK) is a druggable target for cancer therapy. By and large, the oncogenic activation of ALK in human tumors is known to occur by gene rearrangement (e.g. EML4-ALK, NMP-ALK, etc.). Clinical use of ALK inhibitors for “ALK-rearranged” lung cancers has remarkably improved patient survival. To date, much has been known about ALK gene rearrangement in human carcinogenesis and its drug sensitivity relationship. However, emerging genomic data from the Cancer Genome Atlas (TCGA, USA) are now revealing common ALK point mutations (~3.06%) in various cancer types other than lung cancer. Importantly, several recent studies have demonstrated that ALK point mutations, independent of ALK-gene rearrangement, can be oncogenic. Thus, ALK mutations can be pathogenically and perhaps therapeutically important for various cancer types. Here, we summarized the latest ALK mutation frequencies and mutation patterns across 17 human cancer types stemming from TCGA. Unlike many other oncogenes with high frequency of hotspot mutations, ALK point mutations tend to span along the entire gene. Up till now, several recurrent mutations (G263, R401, R551, P968 and E1242) and mutation-rich cluster regions have been identified, but their functional effects remain unknown. We also conducted a comprehensive review of all ALK-mutated human cancer cell lines (from the Cell Line Encyclopedia (CCLE) and the NCI-60 panel), which can be used as model systems for ALK mutation biology and drug screening studies. Lastly, we summarized both the preclinical and clinical findings of ALK mutations on carcinogenesis and drug sensitivity, which may provide important insight into new treatment strategies and prompt future ALK mutation studies in various cancer types.
Export Options
About this article
Cite this article as:
Nick Ka Ming Yau, Andrew Yuon Fong, Hiu Fung Leung, Krista Roberta Verhoeft and Qin Ying Lim, Wai Yip Lam, Ian Chi Kei Wong and Vivian Wai Yan Lui , A Pan-Cancer Review of ALK Mutations: Implications for Carcinogenesis and Therapy, Current Cancer Drug Targets 2015; 15 (4) . https://dx.doi.org/10.2174/1568009615666150225123712
DOI https://dx.doi.org/10.2174/1568009615666150225123712 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Pharmacology of Rhein and Advancement in the Synthesis of Its Derivatives
Current Traditional Medicine Novel Approaches to the Treatment of Obesity and Type 2 Diabetes Mellitus: Bioactive Leptin-Related Synthetic Peptide Analogs
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery (Discontinued) Induction of Senescent-Like Growth Arrest as a New Target in Anticancer Treatment
Current Cancer Drug Targets The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development
Current Molecular Medicine Traversing the Skin Barrier with Nano-emulsions
Current Drug Delivery Recent Patents and Patent Applications Relating to mTOR Pathway
Recent Patents on DNA & Gene Sequences Metformin for Prevention and Treatment of Colon Cancer: A Reappraisal of Experimental and Clinical Data
Current Drug Targets Regulation of Female Fertility and Identification of Future Contraceptive Targets
Current Pharmaceutical Design Meet Our Editorial Board Member:
Current Medicinal Chemistry Recent Advances in Receptor-Targeted Fluorescent Probes for In Vivo Cancer Imaging
Current Medicinal Chemistry Purinergic Signalling: What is Missing and Needed Next? The Use of Transgenic Mice, Crystallographic Analysis and MicroRNA
CNS & Neurological Disorders - Drug Targets Gene Therapy Targeting Nuclear Factor-κB: Towards Clinical Application in Inflammatory Diseases and Cancer
Current Gene Therapy Molecular Response to Hypericin-Induced Photodamage
Current Medicinal Chemistry Structure-Based Approach for the Discovery of Novel Selective Estrogen Receptor Modulators
Current Medicinal Chemistry Recent Advances in Developing K-Ras Plasma Membrane Localization Inhibitors
Current Topics in Medicinal Chemistry Effects of Endocrine Disruptors on Developmental and Reproductive Functions
Current Drug Targets - Immune, Endocrine & Metabolic Disorders Effects of Novel Alkyl Pyridine Platinum Complexes on Apoptosis in Ishikawa Endometrial Cancer Cells
Medicinal Chemistry Tamoxifen: Is it Safe? Comparison of Activation and Detoxication Mechanisms in Rodents and in Humans
Current Drug Metabolism Regulation of the PI3K-Akt Network: Current Status and a Promise for the Treatment of Human Diseases
Current Signal Transduction Therapy The Role of Non-coding Genome in Cancer-associated Fibroblasts; Stateof- the-Art and Perspectives in Cancer Targeted Therapy
Current Drug Targets