Drivers of histologic transformation in EGFR-mutant lung cancer

EGFR 突变肺癌组织学转化的驱动因素

• 批准号: 10302886
• 负责人: CHARLES M RUDIN
• 金额: $ 40.49万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10302886
• 关键词: Address; Adenocarcinoma; Biological Models; Cell Line; Cell Lineage; Cells; Clinical; Clinical Trials; Data; Development; Disease; Disease Progression; Drug resistance; EZH2 gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epigenetic Process; Epithelial Cells; Evolution; Frequencies; Gene Expression Profile; Genetic Transcription; Genomics; Goals; Histologic; Histology; Intervention; Intervention Studies; Libraries; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mediating; Microdissection; Modeling; Molecular; Molecular Analysis; Neoplasm Metastasis; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Pharmacotherapy; Prognosis; Proto-Oncogene Proteins c-akt; RB1 gene; Research Infrastructure; Research Support; Resected; Resistance; Sampling; Solid Neoplasm; Somatic Mutation; Squamous Cell; System; TP53 gene; Therapeutic; Time; Translating; Translational Research; Tumor Tissue; Work; base; bisulfite sequencing; cancer cell; cancer therapy; cell transformation; cell type; chemotherapy; cohort; epigenomics; exome sequencing; high risk; insight; interest; mutant; novel therapeutic intervention; oncogene addiction; patient derived xenograft model; prevent; prospective; resistance mechanism; single cell technology; single-cell RNA sequencing; targeted treatment; transcriptome sequencing; transcriptomics; tumor; tumorigenesis

Project Summary: EGFR-mutant lung cancers (LCs) are initially highly responsive to EGFR inhibitors, but cancer adaptation resulting in drug resistance universally occurs. Acquired resistance mediated by lineage plasticity is particularly problematic; EGFR-mutant lung adenocarcinomas (ACs) can transform into either small cell (SC) or squamous cell (SQ) lung cancers. Understanding the molecular determinants of histologic transformation is critical to inform therapeutic strategies to block the emergence of new cell lineage states induced by cancer treatments. We have established that concurrent alterations in TP53 and RB1 are necessary but not sufficient to induce SC transformation in EGFR-mutant LCs; EGFR/TP53/RB1-mutant LCs have a 25% likelihood of transformation over time. In addition, we have assembled a cohort of resected mixed histology tumors (AC/SC and AC/SQ) that serve as a model of transformation where microdissection by histology isolates paired tumors representing pre- and post- transformation states. Using these complementary systems directly derived from patients, we will perform a mechanistic analysis of lineage plasticity utilizing EGFR/TP53/RB1-mutant LCs at high risk for transformation and mixed histology tumors that represent transformation in progress. Our central hypothesis is that while the somatic mutational landscape is critical in establishing conditions permissive of lineage plasticity, actual transformation to an alternative lineage is predominantly epigenetically driven and associated with consistent globally altered patterns of gene expression. Our first aim is to comprehensively molecularly characterize lineage plasticity using parallel whole exome, RNA and bisulfite sequencing focusing on patient samples from before, during (mixed AC/SC and AC/SQ) and after transformation. Resected mixed histology tumors (AC/SQ) will be microdissected and molecularly characterized as paired tumors. The second aim of the proposal is to investigate subclonal dynamics contributing to lineage plasticity using single cell RNA-sequencing. We will interrogate serial samples from our ongoing clinical trial to prevent transformation in patients with EGFR/TP53/RB1-mutant lung ACs and resected mixed histology AC/SC and AC/SQ tumors. Finally, we will utilize our patient-derived xenograft models of transformation to genetically and pharmacologically assess putative drivers of transformation, exploring rational interventional strategies. Our preliminary work has proposed initial targets (Wnt, EZH2, AKT, NOTCH) that will be expanded with findings from this proposal. Novel therapeutic interventions will be proposed based on our findings that can be rapidly translated to the clinical setting for LC and other disease states characterized by lineage plasticity.

项目概要： EGFR 突变型肺癌 (LC) 最初对 EGFR 抑制剂高度敏感，但癌症适应 导致耐药性普遍发生。由谱系可塑性介导的获得性抗性尤其重要 有问题的； EGFR 突变肺腺癌 (AC) 可转化为小细胞 (SC) 或鳞状细胞癌 细胞（SQ）肺癌。了解组织学转化的分子决定因素对于提供信息至关重要 阻止癌症治疗诱导的新细胞谱系状态出现的治疗策略。我们有 确定 TP53 和 RB1 的同时改变是必要的，但不足以诱导 SC EGFR 突变 LC 的转化； EGFR/TP53/RB1 突变 LC 的转化可能性为 25% 时间。此外，我们还收集了一组切除的混合组织学肿瘤（AC/SC 和 AC/SQ）， 作为转化模型，其中通过组织学进行显微解剖分离出代表前体的配对肿瘤 和转换后状态。使用这些直接源自患者的补充系统，我们将 利用具有高风险的 EGFR/TP53/RB1 突变 LC 对谱系可塑性进行机械分析 转化和混合组织学肿瘤代表正在进行的转化。 我们的中心假设是，虽然体细胞突变景观对于建立条件至关重要 允许谱系可塑性，实际向替代谱系的转变主要是表观遗传的 驱动并与一致的全球改变的基因表达模式相关。我们的首要目标是 使用平行全外显子组、RNA 和亚硫酸氢盐对谱系可塑性进行全面的分子表征 重点关注转化前、转化期间（混合 AC/SC 和 AC/SQ）和转化后的患者样本。 切除的混合组织学肿瘤（AC/SQ）将进行显微解剖并进行配对的分子表征 肿瘤。该提案的第二个目标是研究有助于谱系可塑性的亚克隆动力学 使用单细胞 RNA 测序。我们将询问正在进行的临床试验中的系列样本，以防止 EGFR/TP53/RB1 突变肺 AC 和切除混合组织学 AC/SC 患者的转化 AC/SQ 肿瘤。最后，我们将利用源自患者的异种移植模型进行遗传和转化 药理学评估假定的转化驱动因素，探索合理的干预策略。我们的 初步工作提出了初步目标（Wnt、EZH2、AKT、NOTCH），这些目标将根据以下研究结果进行扩展 这个建议。我们将根据我们的研究结果提出新的治疗干预措施，这些干预措施可以迅速得到实施 转化为 LC 和其他以谱系可塑性为特征的疾病状态的临床环境。