Emergence of drug resistant mutations in lung cancer

肺癌耐药突变的出现

基本信息

批准号：
8984296
负责人：
Susumu Kobayashi
金额：
$ 23.36万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-09 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8984296
关键词：
Accounting Amino Acids Antibody Diversity B-Lymphocytes Base Pairing Binding Cancer Etiology Cancer cell line Cells Cessation of life Chromosomal translocation Clinical Clinical Trials Country Cytidine Deaminase Cytosine DNA Data Development Disease Drug resistance Ectopic Expression Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Family Future Gefitinib Gene Mutation Generations Goals Health Human Immune system Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination In Vitro Lead Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Mediating Methionine Molecular Mutation Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Patient Care Patients Phosphotransferases Play Positioning Attribute RNA Resistance Resistance development Role Signal Transduction Somatic Mutation Testing Threonine Thymine Time Tissues Transforming Growth Factor beta Tyrosine Kinase Inhibitor United States Uracil Xenograft procedure activation-induced cytidine deaminase anticancer research autocrine base c-erbB-1 Proto-Oncogenes cancer therapy clinical care in vivo in vivo Model inhibitor/antagonist insight lung tumorigenesis member mouse model mutant novel novel strategies novel therapeutic intervention novel therapeutics patient population prevent research study response standard care tumor

项目摘要

DESCRIPTION (provided by applicant): Lung cancer continues to lead cancer-related deaths in the United States. During the last decade, it has become clear that somatic gene alterations can cause this deadly disease. The discovery of epidermal growth factor receptor (EGFR) somatic mutations in lung cancer has provided better understanding of tumor formation and ushered the development of tyrosine kinase inhibitors (TKIs) as a standard treatment. However, despite initial dramatic responses, resistance to TKIs emerges within 2 years. Cytosine (C) to thymine (T) single base pair change leads to a threonine to methionine (T790M) amino acid alteration in the ATP-binding pocket of the EGFR. T790M is detected in more than 50% of gefitinib/erlotinib-resistant patients. However, the precise mechanism of emergence of this mutation is not clear. Activation-induced cytidine deaminase (AID) is a B-cell-specific DNA mutator and plays an important role in immune system by creating antibody diversity. Expression and activation of AID is tightly regulated under normal conditions, but aberrant expression of AID in lymphocytes or other tissues can cause cancer by introducing chromosomal translocations and/or mutations. We hypothesize that AID can be induced by EGFR TKIs and creates T790M acquired resistant mutation in EGFR. Therefore, our specific aims are to: (1) Examine whether AID induced by EGFR TKIs leads to emergence of EGFR T790M in vitro and in vivo; and (2) Identify the mechanism by which EGFR TKIs induce AID. We believe that the experiments proposed here will provide novel insights into development of drug resistant mutations in oncogenic kinases and significantly impact care of patients with NSCLC in the near future.

描述（由申请人提供）：肺癌继续导致美国与癌症有关的死亡。在过去的十年中，很明显，体细胞基因改变会导致这种致命的疾病。肺癌中表皮生长因子受体（EGFR）体细胞突变的发现提供了更好地了解肿瘤形成，并将酪氨酸激酶抑制剂（TKIS）的发展作为标准治疗方法。然而，尽管最初的戏剧性反应，但对TKI的抵抗仍在2年内出现。胞嘧啶（C）到胸腺氨酸（T）单碱基对变化导致苏氨酸到EGFR的ATP结合口袋中的蛋氨酸（T790M）氨基酸的蚀变。在超过50％的Gefitinib/erlotinib耐药患者中检测到T790M。但是，这种突变出现的确切机制尚不清楚。激活诱导的胞苷脱氨酶（AID）是B细胞特异性DNA突变器，并通过创建抗体多样性在免疫系统中起重要作用。在正常条件下，AID的表达和激活受到严格的调节，但是淋巴细胞或其他组织中有助的异常表达可以通过引入染色体易位和/或突变来引起癌症。我们假设EGFR TKI可以诱导AID，并在EGFR中产生T790M获得的抗性突变。因此，我们的具体目的是：（1）检查EGFR TKI诱导的援助是否导致EGFR T790M在体外和体内出现；（2）确定EGFR TKI诱导援助的机制。我们认为，这里提出的实验将提供有关致癌激酶耐药突变发展的新颖见解，并在不久的将来会显着影响NSCLC患者的护理。