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: 10689103
• 负责人: Charles M. Rudin
• 金额: $ 39.68万
• 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/10689103
• 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; Pharmacotherapy; Prognosis; Proto-Oncogene Proteins c-akt; Qualifying; RB1 gene; Research; Research Infrastructure; Resected; Resistance; Sampling; Solid Neoplasm; Somatic Mutation; Squamous Cell; Squamous Cell Lung Carcinoma; Squamous Cell Neoplasms; System; TP53 gene; Therapeutic; Time; Translating; Translational Research; Tumor Tissue; Work; bisulfite sequencing; cancer cell; cancer therapy; candidate validation; carcinogenesis; cell transformation; cell type; chemotherapy; cohort; epigenomics; exome sequencing; high risk; insight; interest; mutant; novel therapeutic intervention; oncogene addiction; patient derived xenograft model; permissiveness; pharmacologic; 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，但癌症适应性 导致普遍出现耐药性。由谱系可塑性介导的获得性抗性特别是 EGFR突变型肺腺癌（ACs）可以转化为小细胞（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了解 治疗策略，以阻断由癌症治疗诱导的新细胞谱系状态的出现。我们有 确定TP 53和RB 1的同时改变是必要的，但不足以诱导SC EGFR突变LC的转化; EGFR/TP 53/RB 1突变LC转化的可能性为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）， 作为转化的模型，其中通过组织学显微切割分离出代表前 和转化后的状态。使用这些直接来自患者的补充系统，我们将 利用EGFR/TP 53/RB 1突变型LC进行谱系可塑性的机制分析， 转化和混合组织学肿瘤，代表进行中的转化。 我们的中心假设是，虽然体细胞突变景观是建立条件的关键， 允许谱系可塑性，实际转化为替代谱系主要是表观遗传学的 驱动并与一致的全局改变的基因表达模式相关。我们的首要目标是 使用平行的全外显子组、RNA和亚硫酸氢盐全面地分子表征谱系可塑性 测序集中于转化之前、期间（AC/SC和AC/SQ混合）和之后的患者样本。 将对切除的混合组织学肿瘤（AC/SQ）进行显微解剖，并在分子上表征为配对 肿瘤的该提案的第二个目的是调查亚克隆动态有助于谱系可塑性 使用单细胞RNA测序。我们将从正在进行的临床试验中提取系列样本， EGFR/TP 53/RB 1突变型肺AC和切除的混合组织学AC/SC患者的转化， AC/SQ肿瘤。最后，我们将利用我们的患者来源的异种移植转化模型， 重新评估转型的假定驱动因素，探索合理的干预策略。我们 初步工作已经提出了初步目标（Wnt，EZH 2，AKT，NOTCH），这些目标将随着来自 这个提议。基于我们的发现，将提出新的治疗干预措施， 转化为LC和以谱系可塑性为特征的其他疾病状态的临床环境。