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Role of HER2 mutations in breast cancer progression and response to targeted therapies

HER2 突变在乳腺癌进展和靶向治疗反应中的作用

基本信息

批准号：
10214565
负责人：
Carlos L Arteaga
金额：
$ 36.83万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-07 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214565
关键词：
Antibodies Binding Biochemical Breast Breast Cancer Cell Breast Cancer cell line Breast Cancer therapy Cancer Cell Growth Cancer cell line Candidate Disease Gene Carcinoma Cell Line Cells Clinic Clinical Clinical Research Clinical Trials Combined Modality Therapy Complement Computer Models DNA Sequence Alteration DNA sequencing Dependence Drug Combinations Drug resistance EGFR gene ERBB2 gene ERBB3 gene Epidermal Growth Factor Receptor Estrogen Antagonists Estrogen Receptors Exhibits FRAP1 gene Family member Fulvestrant Gene Amplification Genes Genetic Screening Genotype Goals Growth Health Heterodimerization Human In Vitro Knock-in MCF10A cells MCF7 cell MEKs Malignant Neoplasms Modeling Molecular Molecular Profiling Mus Mutate Mutation Neoplasms Newly Diagnosed Oncogenic PI3K/AKT Pathway interactions Patient-Focused Outcomes Patients Pertuzumab Phase Phosphoproteins Phosphotransferases Population Prognosis Property Protein Array Receptor Protein-Tyrosine Kinases Recurrence Resistance Resistance development Role Sampling Signal Transduction Solid Neoplasm Structural Models Structure Testing Translating Trastuzumab Tyrosine Kinase Inhibitor United States Xenograft procedure breast cancer progression cancer diagnosis cancer subtypes effective therapy established cell line exome sequencing experimental study gain of function genome-wide improved outcome in vivo inhibitor/antagonist knock-down malignant breast neoplasm mortality mutant neutralizing antibody next generation novel patient derived xenograft model patient subsets receptor resistance mechanism response small molecule inhibitor targeted treatment transcriptome sequencing translational impact treatment strategy tumor tumor progression tumorigenesis tumorigenic

项目摘要

ABSTRACT Activating mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase (RTK), occur in ~3% of human tumors and correlate with poor prognosis in breast cancer. Since HER2 mutations usually occur in the absence of HER2 gene amplification, there are currently no approved therapies for this breast cancer subtype. A subset of patients with HER2-mutant breast cancers exhibit excellent clinical responses to anti-HER2 therapies such as the tyrosine kinase inhibitor (TKI) neratinib, suggesting that HER2 mutations are oncogenic drivers. However, the molecular mechanisms by which mutant HER2 promotes breast cancer progression are poorly understood and the response of the most common HER2 mutants to the multiple available anti-HER2 therapies has not been systematically investigated. Finally, durable clinical responses to HER2 TKIs are not the rule and are generally transient, suggesting mechanisms of drug resistance that remain to be discovered. Our objectives are to determine the mechanisms by which mutant HER2 promotes breast cancer oncogenesis and to identify the treatments that are most effective against HER2-mutant breast cancers. We hypothesize that 1) recurrent HER2 mutations generate gain-of-function activity and, as such, tumor dependence on aberrant HER2 signaling, which can be inhibited with targeted therapies; 2) HER2 mutations cooperate with co-occurring mutations in other ERBB RTKs to promote breast cancer growth; and 3) co-occurring genomic alterations will lead to intrinsic or acquired resistance to HER2 TKIs in HER2-mutant cancers. To test these hypotheses, we propose the following three aims: 1) To define mechanisms by which HER2 mutants promote breast oncogenesis and cancer progression; 2) To examine whether HER2 mutations cooperate with alterations in other ERBB RTKs; and 3) To identify mechanisms of resistance to HER2 TKIs in HER2-mutant breast cancers. We propose to integrate structural, biochemical, molecular and in vivo approaches to complete these aims. We will use computational modeling and phospho-protein arrays to determine the mechanisms by which HER2 mutations exert their tumorigenic properties, and will use inhibitors of HER2 signaling to block these effects in HER2-mutant cell lines and patient-derived xenografts (PDXs). We will model cooperation between observed co-occurring mutations in HER2/EGFR and HER2/HER3 in vitro and in vivo. We will employ a genome-wide genetic screen to identify genes that promote resistance to neratinib ± antiestrogens in HER2-mutant breast cancer cells. Finally, we will develop models of acquired resistance to neratinib using HER2-mutant PDXs and identify mechanisms of resistance by next-generation DNA and RNA sequencing, which will be confirmed in patient samples from the SUMMIT clinical trial. These studies will determine the best drug combinations to use in order to inhibit mutant HER2-driven cancer progression and will identify strategies to overcome resistance to HER2 mutation inhibitors. These studies have the potential to be rapidly translated to the clinic and significantly reduce mortality from HER2-mutant cancers.

抽象的 ERBB2（编码 HER2 受体酪氨酸激酶 (RTK) 的基因）的激活突变发生在约 3% 的人中人类肿瘤并与乳腺癌的不良预后相关。由于 HER2 突变通常发生在由于不存在 HER2 基因扩增，目前尚无针对这种乳腺癌亚型的批准疗法。一部分 HER2 突变乳腺癌患者对抗 HER2 药物表现出优异的临床反应酪氨酸激酶抑制剂 (TKI) neratinib 等疗法表明 HER2 突变具有致癌性司机。然而，突变型 HER2 促进乳腺癌进展的分子机制尚不清楚。人们对最常见 HER2 突变体对多种可用抗 HER2 药物的反应知之甚少治疗方法尚未得到系统研究。最后，HER2 TKI 的持久临床反应并不规律并且通常是短暂的，这表明耐药机制仍有待发现。我们的目标是确定突变型 HER2 促进乳腺癌发生的机制并确定针对 HER2 突变乳腺癌最有效的治疗方法。我们假设 1) 反复出现的 HER2 突变会产生功能获得活性，因此，肿瘤对异常的 HER2 信号传导，可以通过靶向治疗来抑制； 2) HER2突变配合其他 ERBB RTK 中同时发生的突变可促进乳腺癌生长； 3) 共存基因组改变将导致 HER2 突变癌症中对 HER2 TKI 产生内在或获得性耐药性。为了检验这些假设，我们提出以下三个目标：1）定义 HER2 的机制突变体促进乳腺肿瘤发生和癌症进展； 2) 检查HER2是否突变配合其他 ERBB RTK 的改造； 3) 确定 HER2 TKI 耐药机制 HER2 突变乳腺癌。我们建议整合结构、生化、分子和体内实现这些目标的方法。我们将使用计算模型和磷蛋白阵列来确定 HER2 突变发挥其致瘤特性的机制，并将使用抑制剂 HER2 信号通路可阻断 HER2 突变细胞系和患者来源的异种移植物 (PDX) 中的这些影响。我们将在体外模拟观察到的 HER2/EGFR 和 HER2/HER3 共发生突变之间的合作体内。我们将采用全基因组遗传筛选来识别促进来那替尼耐药的基因± HER2 突变乳腺癌细胞中的抗雌激素。最后，我们将开发获得性耐药模型 neratinib 使用 HER2 突变 PDX 并通过下一代 DNA 和 RNA 识别耐药机制测序，这将在 SUMMIT 临床试验的患者样本中得到证实。这些研究将确定用于抑制突变 HER2 驱动的癌症进展的最佳药物组合，以及将确定克服 HER2 突变抑制剂耐药性的策略。这些研究有可能迅速转化为临床并显着降低 HER2 突变癌症的死亡率。