HER2基因新型突变与乳腺癌抗HER2靶向治疗耐药的关系及其机制研究

以曲妥珠单抗为代表的抗HER2靶向药物为HER2阳性乳腺癌的治疗带来了重大突破，但原发或继发耐药严重限制了这些药物的疗效。研究HER2阳性乳腺癌对靶向药物的抵抗机制具有重要意义。本项目前期针对HER2阳性乳腺癌配对的原发灶和曲妥珠单抗治疗后的耐药肺转移灶进行全外显子组测序，发现转移灶较之原发灶新增HER2激酶域的新型突变K753E。过表达K753E突变型HER2的乳腺癌细胞对曲妥珠单抗和拉帕替尼耐药。为此我们提出假说：HER2突变通过影响HER2激酶活性引起抗HER2靶向治疗耐药。我们计划以 “HER2新型突变-抗HER2靶向治疗-获得性耐药”为线索，利用配对的原发-耐药转移灶标本、裸小鼠原位移植瘤模型以及人乳腺癌细胞系，研究HER2新型突变调控靶向治疗抵抗的机制。本项目旨在揭示HER2新型突变引起靶向治疗耐药的机制，探索逆转耐药的策略，最终为临床上治疗HER2阳性乳腺癌提供新线索。

Drugs targeting HER2, such as trastuzumab, are a mainstay of breast cancer treatment; however, approximately half of HER2-positive breast cancers exhibit de novo or acquired resistance to these therapies. The mechanisms underlying drug resistance are unclear, and a better understanding of resistance to HER2-targeted therapy is essential for the development of more durable and effective therapeutics. We conducted exome sequencing of the primary and paired metastatic tumors from four patients, identifying novel HER2 mutation (K753E) affecting the kinase domain only in the metastatic lesions of two cases. Stable overexpression of K753E HER2 in breast cancer cell lines resulted in trastuzumab and lapatinib resistance. Taking advantage of paired samples, animal models and cell lines, we plan to study the relationship between novel HER2 mutations and resistance to trastuzumab, lapatinib, and other HER2-targeted drugs. We aim to investigate the roles of novel HER2 mutations in the acquisition of resistance to HER2-targeted therapy, develop new strategies to overcome the resistance and improve outcome of HER2-positive disease.