Molecular ontology of drug tolerant persisters in HER2 positive breast cancer - Resubmission - 1

HER2 阳性乳腺癌耐药者的分子本体论 - 重新提交 - 1

基本信息

批准号：
10391866
负责人：
BENJAMIN G. NEEL
金额：
$ 70.23万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10391866
关键词：
3-Dimensional ATAC-seq Ablation Address Affect Antineoplastic Agents Architecture BT 474 Bar Codes Binding Cancer Biology Cancer Center Cancer Etiology Caspase Cell Line Cells Chimeric Proteins Chromatin Chromatin Loop Chromosome Structures Data Data Analyses Disease remission Drug Combinations Drug Monitoring Drug Tolerance Drug resistance ERBB2 gene Epigenetic Process Exhibits Exposure to Gene Amplification Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Growth In complete remission Malignant Neoplasms Mammalian Cell Mediating Mesenchymal Microscopy Mitosis Modeling Molecular Mus Neoadjuvant Therapy Non-Small-Cell Lung Carcinoma Oncogenes Ontology Pathologic Patients Pharmaceutical Preparations Phenotype Play Population Receptor Protein-Tyrosine Kinases Reporter Resistance Resolution Role Sampling Signal Transduction Testing Time Tyrosine Kinase Inhibitor Work Xenograft procedure Yeasts cancer type chemotherapy clinical efficacy cohesin condensin conventional therapy in vivo Model insight lapatinib malignant breast neoplasm melanoma mouse model non-genetic novel novel therapeutics patient derived xenograft model prevent programs promoter senescence targeted treatment transcription factor TFIIIC transcriptome transcriptome sequencing tumor tumor growth tumor-immune system interactions

项目摘要

SUMMARY: “Targeted therapies” against “driver oncogenes” play key roles in the therapy of many tumors, including breast cancers caused by amplification of the gene encoding the receptor tyrosine kinase HER2 (HER2+ BC). In metastatic HER2+ BC, however, resistance occurs even to combinations of anti-cancer drugs, and preventing its emergence is essential for converting remissions to cures. “Drug-tolerant persisters” (DTPs) survive exposure to tyrosine kinase inhibitors (TKIs) and other anti-neoplastics in a non-proliferative, quiescent (dormant) state via reversible, non-genetic mechanisms. DTPs are implicated in resistance of EGFRmut non-small cell lung cancer (NSCLC), BRAFmut melanoma, and other cancers, but a potential role in in HER2+ BC had not been explored thoroughly. We found that HER2+ BC lines treated with HER2-TKIs (lapatinib, tucatinib) give rise to two types of DTPs, which have luminal or mesenchymal transcriptomes. As in other cell lines, a fraction of HER2+ BC cells transit stochastically through G0 after exiting mitosis, instead of proceeding directly into G1. Remarkably, luminal DTPs arose uniquely from these transient G0 cells (“pre- DTPs”), which also express a subset of DTP genes. HER2+ BCs are highly proliferative, yet like other tumors, they also have significant numbers of G0 (Ki67-) cells, and our initial analyses of samples from TKI-treated HER2+ BC patients comport with DTP generation from G0 cells. Thus, in contrast to current models, which contend that the drug-tolerant, quiescent state is induced by TKIs and other targeted therapies/chemotherapies, our data indicate that pre-DTPs might already be present in the drug-naïve population. We hypothesize that the chromatin of such transient, G0/pre-DTP cells has a globally distinct organization that primes them to induce the complete DTP transcriptome and become drug-tolerant upon TKI exposure. Whether this “G0 selection/induction” model applies to mesenchymal-like HER2+ DTPs, DTPs induced by other agents, and/or more broadly to bona fide HER2 tumors remains unclear. Because DTPs comprise a potential cellular reservoir for seeding stable resistance to HER2 TKIs and other targeted/conventional therapies, delineating their ontogenetic mechanisms could reveal novel cancer vulnerabilities and ultimately, new therapies. Our focus on the unique features of gene regulation in G0 cells could also have implications for tumor dormancy. This proposal joins experts in epigenetics/chromosome organization (SKOK) and cancer biology/cell signaling (NEEL) to address these timely, relevant questions Specifically, we will: (1) Characterize chromatin architecture and gene regulation in HER2-TKI pre-DTPs and DTPs from luminal-like HER2+ BC lines, (2) Test the hypothesis that HER2-TKI DTPs from mesenchymal HER2+ BC lines also arise from G0-like pre-DTPs and have condensin II-organized chromatin, and (3) Test the pathophysiological significance of lapatinib DTPs in in vivo models of HER2-TKI DTPs.

摘要：针对“驱动癌基因”的“靶向治疗”在许多肿瘤的治疗中发挥着关键作用，包括由编码受体酪氨酸激酶 HER2 的基因扩增引起的乳腺癌 (HER2+ BC) 然而，在转移性 HER2+ BC 中，甚至对抗癌组合也会产生耐药性。 “耐药者” （DTP）在非增殖性、通过可逆的、非遗传机制的静止（休眠）状态与耐药性有关。 EGFRmut 非小细胞肺癌 (NSCLC)、BRAFmut 黑色素瘤和其他癌症，但在以下方面具有潜在作用我们发现 HER2+ BC 用 HER2-TKIs 治疗品系。（拉帕替尼、图卡替尼）产生两种类型的 DTP，它们具有管腔或间充质转录组 As。在其他细胞系中，一小部分 HER2+ BC 细胞在退出有丝分裂后随机通过 G0，而不是值得注意的是，管腔 DTP 是从这些短暂的 G0 细胞中独特产生的。 HER2+ BC 具有高度增殖性，但与其他肿瘤一样，它们还具有大量的 G0 (Ki67-) 细胞，我们对经过 TKI 处理的样品进行了初步分析 HER2+ BC 患者符合 G0 细胞的 DTP 生成，因此与当前模型相反。认为耐药的静止状态是由 TKI 和其他靶向药物诱导的疗法/化疗，我们的数据表明，DTP 前可能已经存在于未接受过药物治疗的患者中。人口。我们追求这种瞬时的 G0/DTP 前细胞的染色质具有全局独特的组织，使它们能够诱导完整的 DTP 转录组并在 TKI 暴露。这种“G0 选择/诱导”模型是否适用于间充质样 HER2+ DTP、DTP 由其他药物诱导，和/或更广泛地诱导真正的 HER2 肿瘤仍不清楚，因为 DTP 仍不清楚。包含一个潜在的细胞库，用于播种对 HER2 TKI 和其他药物的稳定耐药性靶向/传统疗法，描绘其个体发生机制可以揭示新的癌症我们关注 G0 细胞基因调控的独特特征。该提案与表观遗传学/染色体专家一起提出。组织 (SKOK) 和癌症生物学/细胞信号传导 (NEEL) 来解决这些及时的相关问题具体来说，我们将： (1) 表征 HER2-TKI pre-DTP 中的染色质结构和基因调控来自管腔样 HER2+ BC 系的 DTP，(2) 检验来自间充质细胞系的 HER2-TKI DTP 的假设 HER2+ BC 系也源自 G0 样前 DTP，并具有凝缩蛋白 II 组织的染色质，并且 (3) 测试拉帕替尼 DTP 在 HER2-TKI DTP 体内模型中的病理生理学意义。