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：
9614453
负责人：
Carlos L Arteaga
金额：
$ 38.26万
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/9614453
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 Simulation 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 Property Protein Array Receptor Protein-Tyrosine Kinases Recurrence Resistance Resistance development Role Sampling Signal Transduction Solid Neoplasm Structural Models 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 outcome forecast patient subsets profiles in patients 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.

抽象的激活ERBB2中的突变，编码HER2受体酪氨酸激酶（RTK）的基因发生在〜3％人类肿瘤与乳腺癌预后不良相关。由于HER2突变通常发生在缺乏HER2基因扩增，目前尚无该乳腺癌亚型的批准疗法。一部分患有HER2突变乳腺癌的患者对抗HER2暴露了出色的临床反应诸如酪氨酸激酶抑制剂（TKI）Neratinib之类的疗法，表明HER2突变是致癌的司机。但是，突变体HER2促进乳腺癌进展的分子机制是最常见的理解和最常见的HER2突变体对多种可用抗HER2的反应疗法尚未系统地研究。最后，对HER2 TKI的持久临床反应不是该规则且通常是短暂的，表明尚待发现的耐药性机制。我们的目标是确定突变体HER2促进乳腺癌的机制并确定对HER2突变乳腺癌最有效的治疗方法。我们假设 1）复发性HER2突变会产生功能收益活性，因此肿瘤依赖于异常的HER2信号传导，可以通过靶向疗法抑制； 2）HER2突变与其他ERBB RTK的共发生突变，以促进乳腺癌的生长； 3）共发生的基因组改动将导致HER2突变癌中对HER2 TKI的内在或获得的抵抗力。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癌发生和癌症进展； 2）检查HER2突变是否与其他ERBB RTK的更改合作； 3）确定对HER2 TKI的抗性机制 HER2突变乳腺癌。我们建议整合结构，生化，分子和体内完成这些目标的方法。我们将使用计算建模和磷酸蛋白阵列确定HER2突变执行其肿瘤特性的机制，并将使用抑制剂 HER2信号传导以阻止HER2突变细胞系和患者衍生的Xenographtics（PDXS）中的这些效果。我们将在HER2/EGFR中观察到的共发生突变与HER2/HER3的体外和HER3和体内。我们将采用全基因组遗传筛选来鉴定促进对Neratinib±±±的基因 HER2突变乳腺癌细胞中的抗雌激素。最后，我们将开发出获得的抵抗模型 Neratinib使用HER2突变pDX，并通过下一代DNA和RNA识别抗药性机制测序，将在峰会临床试验中的患者样本中确认。这些研究会确定最佳使用的药物组合，以抑制突变的HER2驱动癌症进展和将确定克服对HER2突变抑制剂的抵抗力的策略。这些研究有可能迅速将其转化为诊所，并显着降低Her2突变癌的死亡率。