Overcoming resistance to tyrosine kinase inhibitors in lung cancer

克服肺癌对酪氨酸激酶抑制剂的耐药性

基本信息

批准号：
9231401
负责人：
Susumu Kobayashi
金额：
--
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：
2013
资助国家：
美国
起止时间：
2013-03-06 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9231401
关键词：
Amino Acids Binding Cancer Etiology Cancer cell line Cells Cessation of life Clinical Clinical Research Complex Development Diagnostic radiologic examination Dissociation E-Cadherin EGF gene Effectiveness Epidermal Growth Factor Receptor Erlotinib Future Gatekeeping Gefitinib Genes Goals Growth Growth Factor Human Lead Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Methionine Modeling Mus Mutation Non-Small-Cell Lung Carcinoma Nuclear Translocation Oncogenic Pathway interactions Patient Care Patients Play Positioning Attribute Proto-Oncogene Proteins c-akt Reporter Resistance Role Signal Transduction Somatic Mutation Testing Threonine Transgenic Mice Transplantation Tyrosine Kinase Domain Tyrosine Kinase Inhibitor Tyrosine Phosphorylation United States Work alpha catenin base beta catenin cancer cell cancer therapy chemotherapy experimental study glycogen synthase kinase 3 beta in vivo inhibitor/antagonist innovation insight lung tumorigenesis mouse model mutant novel novel strategies novel therapeutic intervention novel therapeutics personalized medicine prevent public health relevance receptor response small molecule standard care targeted treatment tumor tumor growth tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The discovery of somatic mutations in epidermal growth receptor (EGFR) in patients who show dramatic response to reversible EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib has introduced the concept of "personalized therapy in lung cancer treatment. However, resistance to the inhibitors emerges within one to two years. The secondary EGFR-T790M mutation, in the "gate-keeper" position of the tyrosine kinase domain, is present in more than 50% of lung cancers with acquired resistance to gefitinib or erlotinib. Since treatment options for these patients are currently limited, novel strategies to prevent or overcome acquired resistance to EGFR TKIs are sorely needed. We have demonstrated that ß-catenin is upregulated and activated in lung cancer cells harboring EGFR mutations including EGFR-T790M. As aberrant activation of ß-catenin signaling can lead to human cancers, we hypothesize that ß-catenin plays an essential role in lung tumorigenesis caused by EGFR mutants and inhibiting its activation alone or in combination with irreversible EGFR inhibitors may be an alternative strategy to overcome resistance to gefitinib or erlotinib. Therefore, our specific aims are to: (1) Investigate the mechanisms by which EGFR mutants lead to accumulation, nuclear translocation, and activation of �-catenin; (2) Investigate whether activation of ß-catenin is required for EGFR- T790M-driven lung cancer formation/progression in vivo; and (3) Evaluate the effectiveness of ß-catenin inhibition as a novel therapeutic strategy to overcome resistance to erlotinib or gefitinib. We believe that the experiments proposed here will provide novel insights into the detailed mechanisms by which EGFR mutations cause tumorigenesis and innovative approaches to overcome resistance to gefitinib or erlotinib, significantly impacting care of patients with lung cancer in the near future.

描述（适用提供）：在表皮生长受体（EGFR）中发现对可逆的EGFR EGFR酪氨酸激酶抑制剂（TKIS）Gefitinib或Erlotinib的剧烈反应的患者发现了体细胞突变。但是，在肺癌治疗中，“抗癌症”的概念是在肺癌中的7年中介绍了一个syne-necrions news in news in news in newne newne news in newne news news newne news in news in unipers in nection。在酪氨酸激酶结构域的“守门员”位置中，在超过50％的肺癌中存在对吉法替尼或erlotinib的抗性，因为这些患者的治疗选择是有限的，可以预防或克服对EGFR TKIS的抗药性。包括EGFR-T790M。因此，我们的具体目的是：（1）研究EGFR突变体导致累积，核易位和钙蛋白激活的机制；（2）研究EGFR-T790M驱动的肺癌形成/体内进展是否需要β-catenin的激活；（3）评估β-catenin抑制作用作为一种新型治疗策略的有效性克服对厄洛替尼或吉非替尼的抗性。我们认为，此处提出的实验将提供有关EGFR突变引起肿瘤发生和创新方法的详细机制的新见解，以克服对Gefitinib或Erlotinib的抵抗力，从而在不久的将来对肺癌患者的护理产生显着影响。