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.

项目摘要： EGFR突变肺癌（LCS）最初对EGFR抑制剂有很高的反应，但是癌症适应性 普遍发生耐药性。谱系可塑性介导的获得的电阻尤其是 有问题； EGFR突变肺腺癌（AC）可以转变为小细胞（SC）或鳞状 细胞（SQ）肺癌。了解组织学转化的分子决定因素对于告知 癌症治疗引起的新细胞谱系状态的出现的治疗策略。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突变的LCS转换； egfr/tp53/rb1突变液LC具有25％的转化可能性 时间。此外，我们组装了一组切除的混合组织学肿瘤（AC/SC和AC/SQ） 用作转化模型，通过组织学分离株进行显微解剖配对，代表了前的肿瘤 和后转化状态。使用直接从患者得出的这些互补系统，我们将 利用EGFR/TP53/RB1突变的LCS对谱系可塑性进行机械分析，高风险 转化和混合组织学肿瘤，代表正在进行的转化。 我们的核心假设是，尽管躯体突变景观对于建立条件至关重要 允许的谱系可塑性，实际转化为替代血统的表现主要是表观遗传的 驱动并与一致的全球基因表达模式相关联。我们的第一个目标是 使用平行的整个外显子，RNA和Bisulfite，全面地表征了谱系可塑性 从之前，在（混合AC/SC和AC/SQ）和转化后重点关注患者样本。 切除的混合组织学肿瘤（AC/SQ）将被微分解并分子表征为配对 肿瘤。该提案的第二个目的是研究有助于谱系可塑性的亚克隆动力学 使用单细胞RNA序列。我们将从我们正在进行的临床试验中询问连续样品，以防止 EGFR/TP53/RB1突变肺ACS的患者转化，并切除的组织学AC/SC和 AC/SQ肿瘤。最后，我们将利用我们的患者衍生的异种移植转化模型，以遗传和 药理学评估转型的推定驱动因素，探索合理的介入策略。我们的 初步工作提出了最初的目标（Wnt，Ezh2，Akt，Notch），该目标将随着发现的结果而扩展 这个建议。根据我们的发现，将提出新颖的治疗干预措施 转化为以谱系可塑性为特征的LC和其他疾病状态的临床环境。