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: 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
• 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

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。