Mechanisms of Mutant Epidermal Growth Factor Receptor Induced Lung Tumorigenesis

描述（由申请人提供）：项目摘要。该提案描述了一个培训计划，为候选人的学术生涯在癌症生物学的发展。在整个获奖期间，候选人将开发她的独立研究计划。她还将利用这段时间来建立她的科学知识和指导技能。候选人将由Harold Varmus博士指导，他是癌症生物学领域的领导者，培养了许多成功的科学家。纪念斯隆-凯特琳癌症中心（MSKCC）将提供机构支持，包括充足的资源，职业发展活动以及科学家和临床医生之间的互动机会，以帮助候选人实现她的目标。 该研究的重点是肺癌，这是世界上最常见的癌症。该候选人最近基于肺上皮细胞中突变型表皮生长因子受体（EGFR）的表达产生了两种肺癌小鼠模型。她已经确定，肺癌相关的EGFR突变体可以启动肺肿瘤发生，并为肿瘤维持所需。 本研究计划的目的是确定EGFR突变型肺肿瘤的表型和临床行为如何受到以下因素的影响：1）EGFR表达水平; 2）其他EGFR家族成员的存在; 3）协同遗传病变。具体目标是使用这些新的小鼠模型：1）阐明突变EGFR诱导肺上皮细胞转化的机制; 2）鉴定在肺肿瘤发生中与突变EGFR合作的基因。小鼠模型中的发现将在人类肺癌标本中得到验证。 本案无关EGFR突变在美国约10%的非小细胞肺癌病例中发现，并与酪氨酸激酶抑制剂吉非替尼和厄洛替尼的敏感性相关。该提案解决了与该肺癌子集直接相关的问题：1）EGFR突变体如何转化肺细胞？2)为什么一些EGFR突变的肿瘤患者对酪氨酸激酶抑制剂治疗无反应？3)酪氨酸激酶抑制剂治疗获得性耐药的原因是什么？

DESCRIPTION (provided by applicant): Project Summary. This proposal describes a training program for the development of the candidate's academic career in cancer biology. Throughout the period of this award, the candidate will develop her independent research program. She will also use this time to build on her scientific knowledge and mentoring skills. The candidate will be mentored by Dr. Harold Varmus, a leader in the field of cancer biology who has trained numerous successful scientists. Memorial Sloan-Kettering Cancer Center (MSKCC) will provide institutional support, including ample resources, career development activities and opportunities for interactions between scientists and clinicians to help the candidate achieve her goals. The research focuses on lung cancer, the most common cancer worldwide. The candidate has recently generated two mouse models of lung cancer based on expression of mutant Epidermal Growth Factor Receptors (EGFRs) in lung epithelial cells. She has established that the lung cancer-associated EGFR mutants can initiate lung tumorigenesis and are required for tumor maintenance. The goals of this research proposal are to determine how the phenotype and clinical behavior of EGFR mutant lung tumors are influenced by: 1) the levels of expression of EGFR; 2) the presence of other EGFR family members; and, 3) cooperating genetic lesions. The specific aims are to use these new mouse models to: 1) Elucidate the mechanisms of mutant EGFR-induced transformation of lung epithelial cells; and, 2) Identify genes that cooperate with mutant EGFR in lung tumorigenesis. Findings in the mouse models will be verified in human lung cancer specimens. Relevance. EGFR mutations are found in approximately 10% of non-small cell lung cancer cases in the US and are associated with sensitivity to the tyrosine kinase inhibitors, gefitinib and erlotinib. This proposal addresses questions directly relevant to this subset of lung cancers: 1) How do the EGFR mutants transform lung cells? 2) Why do some patients who have tumors with EGFR mutations NOT respond to tyrosine kinase inhibitor treatment? 3) What are the causes of acquired resistance to tyrosine kinase inhibitor treatment?