Emergence of drug resistant mutations in lung cancer

描述（由申请人提供）：肺癌继续在美国导致癌症相关死亡。在过去的十年里，已经很清楚体细胞基因的改变会导致这种致命的疾病。肺癌中表皮生长因子受体（EGFR）体细胞突变的发现为肿瘤形成提供了更好的理解，并引领了酪氨酸激酶抑制剂（TKIs）作为标准治疗的发展。然而，尽管最初反应显著，但对tki的耐药性在2年内出现。胞嘧啶(C)到胸腺嘧啶(T)单碱基对的改变导致EGFR atp结合口袋中苏氨酸到蛋氨酸（T790M）氨基酸的改变。在超过50%的吉非替尼/厄洛替尼耐药患者中检测到T790M。然而，这种突变出现的确切机制尚不清楚。激活诱导胞苷脱氨酶（Activation-induced cytidine deaminase， AID）是一种b细胞特异性DNA突变体，通过产生抗体多样性在免疫系统中发挥重要作用。AID的表达和激活在正常情况下受到严格调控，但AID在淋巴细胞或其他组织中的异常表达可通过引入染色体易位和/或突变而导致癌症。我们假设AID可以由EGFR TKIs诱导，并在EGFR中产生T790M获得性耐药突变。因此，我们的具体目的是：(1)在体外和体内研究EGFR TKIs诱导的AID是否会导致EGFR T790M的出现；(2)确定EGFR TKIs诱导AID的机制。我们相信，这里提出的实验将为致癌激酶耐药突变的发展提供新的见解，并在不久的将来显著影响NSCLC患者的护理。

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.