Emergence of drug resistant mutations in lung cancer

描述（由申请人提供）：在美国，肺癌继续导致癌症相关死亡。在过去的十年中，体细胞基因改变可以导致这种致命的疾病已经变得很清楚。肺癌中表皮生长因子受体（EGFR）体细胞突变的发现为肿瘤形成提供了更好的理解，并将酪氨酸激酶抑制剂（TKI）作为标准治疗方法开发。然而，尽管最初有戏剧性的反应，对TKI的耐药性在2年内出现。胞嘧啶（C）至胸腺嘧啶（T）的单碱基对变化导致EGFR ATP结合口袋中的苏氨酸至甲硫氨酸（T790 M）氨基酸变化。在超过50%的吉非替尼/厄洛替尼耐药患者中检测到T790 M。然而，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）是一种B细胞特异性DNA突变因子，通过产生抗体多样性在免疫系统中发挥重要作用。AID的表达和活化在正常条件下受到严格调控，但淋巴细胞或其他组织中AID的异常表达可通过引入染色体易位和/或突变而引起癌症。我们假设AID可由EGFR TKI诱导并在EGFR中产生T790 M获得性耐药突变。因此，我们的具体目标是：（1）检查EGFR TKI诱导的AID是否导致EGFR T790 M在体外和体内出现;（2）确定EGFR TKI诱导AID的机制。我们相信，本文提出的实验将为致癌激酶耐药突变的发展提供新的见解，并在不久的将来对NSCLC患者的护理产生重大影响。

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.