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

• 批准号: 10545025
• 负责人: BENJAMIN G. NEEL
• 金额: $ 68.93万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10545025
• 关键词: 3-Dimensional; Ablation; Address; Adjuvant Study; Affect; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Architecture; BT 474; Bar Codes; Binding; Cancer Biology; Cancer Center; Cancer Etiology; Caspase; Cell Line; Cells; ChIP-seq; Chimeric Proteins; Chromatin; Chromatin Loop; Chromosome Structures; Data; 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; 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; Role; Sampling; Signal Transduction; Testing; Tyrosine Kinase Inhibitor; Visualization; 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; superresolution microscopy; targeted treatment; transcription factor TFIIIC; transcriptome; transcriptome sequencing; tumor; tumor growth; tumor-immune system interactions

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“驱动器癌基因”的“有针对性疗法”在许多肿瘤的治疗中起关键作用， 包括由编码受体酪氨酸激酶HER2的基因的扩增引起的乳腺癌 （HER2+ BC）。然而，在转移性HER2+ BC中，抗药性甚至是抗癌的组合 药物和防止其出现对于将缓解恢复到治疗方法至关重要。 “容忍毒品” （DTP）在非增生剂中的酪氨酸激酶抑制剂（TKIS）和其他抗神经塑料中的暴露均能生存 通过可逆的非遗传机制静止（休眠）状态。 DTP隐含在电阻中 EGFRMUT非小细胞肺癌（NSCLC），BRAFMUT黑色素瘤和其他癌症，但在 在HER2+ BC中，尚未进行彻底探索。我们发现用HER2-TKIS处理的HER2+ BC线 （Lapatinib，Tucatinib）产生两种类型的DTP，它们具有腔内或间质转录组。作为 在其他细胞系中，退出有丝分裂后通过G0随机交易的HER2+ BC细胞的一部分，而是 直接进入G1。值得注意的是，Luminal DTPS来自这些瞬态G0细胞（“ Pre- DTP”），也表达DTP基因的子集。HER2+ BC是高度增殖的，但是像其他肿瘤一样， 它们还具有大量的G0（Ki67-）细胞，我们对TKI处理的样品进行了初步分析 HER2+ BC患者与G0细胞的DTP相融合。与当前模型相比 争辩说，耐药的静态状态是由TKI诱导的，其他有针对性的 疗法/化学疗法，我们的数据表明dTP可能已经存在于药物中 人口。 我们假设这种瞬态，G0/pre-DTP细胞的染色质具有全球不同的 组织他们诱导完整的DTP转录组并变得耐药的组织 TKI暴露。该“ G0选择/归纳”模型是否适用于间充质样HER2+ DTP，DTPS 由其他药物和/或更广泛地诱导的是真正的HER2肿瘤，尚不清楚。因为DTP 包括一个潜在的细胞晶状体，用于播种对HER2 TKI和其他的稳定耐药性 靶向/常规疗法，描述其个体发育机制可能揭示了新的癌症 脆弱性，最终是新疗法。我们关注G0细胞基因调节的独特特征 也可能对肿瘤休眠有影响。该建议与表观遗传学/染色体的专家一起 组织（SKOK）和癌症生物学/细胞信号传导（NEEL），以解决这些及时的相关问题 具体而言，我们将：（1）表征HER2-TKI Pre-DTPS中的染色质结构和基因调节 来自Luminal样HER2+ BC线的DTP，（2）检验了Messectemal的HER2-TKI DTP的假设 HER2+ BC线也来自类似于G0的Pre-DTP，并具有凝结蛋白II与组织的染色质，并且（3）测试 Lapatinib DTPS在HER2-TKI DTPS的体内模型中的病理生理意义。