权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

YAP1 and RB1 cooperate to regulate lung cancer lineage plasticity and therapeutic resistance

YAP1和RB1合作调节肺癌谱系可塑性和治疗耐药性

基本信息

批准号：
10829724
负责人：
DAVID W. GOODRICH
金额：
$ 8.59万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10829724
关键词：
Acceleration Adenocarcinoma Cell Affect Alveolar Binding Bypass Caring Cell Line Cell Proliferation Cell Survival Cells Clinical Collaborations DNA Sequence Alteration Data Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epigenetic Process Experimental Models Exposure to Frequencies Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Genetic Determinism Genetic Epistasis Genetic Transcription Genetically Engineered Mouse Goals Human In Vitro Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Mesenchymal Modeling Molecular Mouse Strains Mutation Nature Neurosecretory Systems Non-Malignant Oncogenic Organoids Patient Care Patient-Focused Outcomes Patients Pharmaceutical Preparations Play RB1 gene Recurrence Research Research Personnel Residual Neoplasm Resistance Role Sampling Signal Pathway Signal Transduction Specimen Study models TP53 gene Testing Therapeutic Variant acquired drug resistance cancer cell clinically relevant experimental study genetically modified cells improved in vivo inhibitor therapy interest loss of function mutation mutant non-genetic novel off-target mutation programs response standard of care synergism targeted treatment therapeutic development therapeutic gene therapy outcome therapy resistant transdifferentiation treatment response tumor microenvironment tumor-immune system interactions virtual

项目摘要

PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. Patients with EGFR mutant lung adenocarcinoma (LUAD) are treated with EGFR tyrosine kinase inhibitors (TKI) because they yield better patient outcomes than previous standards of care. EGFR TKI are not curative, however, as virtually all patients progress on therapy due to acquired drug resistance. While genetic mechanisms of acquired EGFR TKI resistance are well understood, non-genetic mechanisms also play an important role. Dynamic and reversible transcriptional adaptations involving lineage state changes support the survival and progression of LUAD cells during treatment. The mechanisms and genetic determinants controlling this LUAD lineage plasticity are not well understood. Advancing fundamental understanding of LUAD lineage plasticity is a prerequisite for the development of therapeutic approaches to predict it, suppress it, and improve therapeutic outcomes. Through analysis of both clinical specimens and experimental models, the collaborating investigators have discovered that minimal residual disease surviving EGFR TKI shows induction of a quiescent, alveolar lineage state. This state is lost in cells proliferating and progressing through EGFR TKI and is replaced by alternative lineage states less dependent on oncogenic EGFR signaling. In currently parallel lines of research within the collaborating investigators labs, YAP1 activity has been demonstrated to drive the alveolar lineage state while RB1 loss accelerates the further transition to alternative, EGFR independent lineage states. These findings suggest YAP1 and RB1 interact to control lineage state transitions during EGFR TKI therapy that ultimately facilitate acquired therapeutic resistance. This ARTNET supplement application is proposed to support collaborative research in two specific aims that will test this hypothesis and validate new genetically engineered mouse models for studying LUAD lineage plasticity in vivo, additionally enabling the study of how non-malignant cells within the tumor microenvironment influence LUAD lineage plasticity and vice versa.

项目摘要本申请是为了响应被标识为NOT-CA的特别利益通知（NOSI）而提交的- 23-045. EGFR突变型肺腺癌（LUAD）患者接受EGFR酪氨酸激酶治疗抑制剂（TKI），因为它们比以前的护理标准产生更好的患者结果。EGFR TKI不是然而，由于几乎所有患者由于获得性耐药性而在治疗中进展，因此是治愈性的。而遗传获得性EGFR TKI耐药的机制已被充分理解，非遗传机制也起作用，重要的作用涉及谱系状态变化的动态和可逆的转录适应支持治疗期间LUAD细胞的存活和进展。遗传因素和控制机制这种LUAD谱系可塑性还没有很好地理解。推进对LUAD谱系的基本理解可塑性是开发治疗方法的先决条件，以预测它，抑制它，治疗结果。通过对临床标本和实验模型的分析，研究者已经发现存活EGFR TKI的最小残留疾病显示诱导静止，肺泡谱系状态这种状态在通过EGFR TKI增殖和进展的细胞中丢失，通过替代谱系状态较少依赖于致癌EGFR信号传导。在目前平行的研究中，在合作的研究者实验室中，已经证明YAP 1活性驱动肺泡谱系而RB 1缺失加速了向替代的EGFR非依赖性谱系状态的进一步转变。这些研究结果表明，在EGFR TKI治疗期间，YAP 1和RB 1相互作用以控制谱系状态转换，最终促进获得性治疗抗性。本ARTNET补充申请旨在支持在两个具体目标的合作研究，将测试这一假设，并验证新的遗传用于研究体内LUAD谱系可塑性的工程小鼠模型，另外还能够研究肿瘤微环境中的非恶性细胞影响LUAD谱系可塑性，反之亦然。