(PQ7) Defining a new mode of RAS signaling in cancer from cytoplasmic protein granules

(PQ7)从细胞质蛋白颗粒定义癌症中RAS信号传导的新模式

• 批准号: 10431980
• 负责人: Trever G Bivona
• 金额: $ 44.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431980
• 关键词: ALK gene; Automobile Driving; Binding Proteins; Biochemistry; Biological; Biological Process; Biophysics; Cancer Control; Cause of Death; Cell membrane; Cells; Cellular biology; Clinical; Cytoplasm; Cytoplasmic Granules; Cytoplasmic Protein; Data; Dependence; Drug resistance; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Event; Exhibits; Future; Gene Fusion; Gene Rearrangement; Genetic; Goals; Growth; In Vitro; KRAS2 gene; Knowledge; Light; Lung Adenocarcinoma; MAP Kinase Gene; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Mammalian Cell; Membrane Lipids; Methods; Molecular; Mutation; Nature; Oncogenes; Oncogenic; Oncoproteins; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phosphotransferases; Proteins; Proteomics; Public Health; Ras/Raf; Regulation; Resistance; Role; Signal Transduction; Specimen; Structure; Subcellular structure; System; Testing; Therapeutic; Time; Work; base; biophysical properties; cancer initiation; clinically relevant; design; diagnostic strategy; improved; interdisciplinary approach; link protein; molecular diagnostics; mutant; novel diagnostics; novel therapeutic intervention; precision medicine; protein function; receptor; reconstitution; recruit; response; targeted cancer therapy; targeted treatment; tumor progression; tumorigenesis

Project Summary As knowledge of the molecular drivers of oncogenesis and tumor progression has grown, so too has our ability to deploy more effective and less toxic molecular therapies. For example, targeted cancer therapies such as ALK and EGFR inhibitors in lung cancer are leading to improved clinical outcomes. However, not all patients benefit from this emerging precision medicine approach, such as patients with KRAS-mutant cancers, and those patients who do benefit initially from targeted therapy ultimately succumb to tumor progression due to drug resistance. Gaining a better understanding of the aberrant cell signaling regulation driving cancer initiation, progression, and drug resistance is essential to expand, and improve, molecular treatment options for patients to extend their survival. A major gap in the field is that very little is known about the potential presence and function of subcellular structures that can organize cell signaling in a cancer-specific manner to promote cancer pathogenesis. By studying the molecular determinants of response and resistance to ALK targeted therapy in ALK gene rearrangement lung adenocarcinoma, we discovered that oncogenic ALK gene rearrangements are uniquely and exquisitely dependent on RAS-RAF-MEK-ERK (RAS/MAPK) signaling for growth and survival. Our studies revealed that the basis of the dependence is that this oncogenic ALK activates RAS from an intracellular, cytoplasmic compartment instead of a lipid-membrane compartment in cells. This was surprising because receptor kinases such as native ALK and RAS both canonically signal exclusively from a lipid-membrane compartment such as the plasma membrane. Our findings prompt the intriguing hypothesis that RAS signaling can occur from a protein granule in the cytoplasm, rather than a lipid- membrane compartment in certain cancers. We propose four Specific Aims that leverage genetic, proteomic, biophysical, and cell biological studies to test this hypothesis, with the goal of demonstrating for the first time in mammalian cells that RAS signaling can emanate from the cytoplasm, in an organized protein-based structure that lacks lipid-membranes. We will test this hypothesis initially in lung cancers with oncogenic ALK and expand to those with oncogenic signaling caused by other aberrant kinase gene fusions that may signal from a similar intracellular protein-based platform. If our hypothesis is true, the findings will transform our understanding of the molecular basis of cancer and overturn 25 years of dogma that holds that RAS signaling can only occur from a lipid-membrane compartment. The findings will generate a new understanding of the role of protein granules in cancer pathogenesis, thereby ascribing an unanticipated biological function for this emerging class of subcellular structures. Our efforts hold important implications for designing entirely novel diagnostic and therapeutic strategies to exploit the pathognomonic subcellular organization of oncogenic signaling to improve treatment options for patients in the future. This project could have broad impacts on the understanding of cancer pathogenesis and pave the way for new molecular strategies to better control cancer.

项目摘要 随着对肿瘤发生和肿瘤进展的分子驱动因素的了解，我们的能力也有所增长 部署更有效和毒性的分子疗法。例如，有针对性的癌症疗法，例如 肺癌中的ALK和EGFR抑制剂可改善临床结果。但是，并非所有患者 受益于这种新兴的精确医学方法，例如Kras突变癌的患者， 那些最初从靶向治疗中受益的患者最终屈服于肿瘤的进展 耐药性。更好地了解驱动癌症的异常细胞信号调节 开始，进展和耐药性对于扩展和改善分子治疗方案至关重要 患者延长生存。该领域的一个主要差距是对潜在存在知之甚少 亚细胞结构的功能，可以以癌症特异性组织细胞信号传导以促进 癌症发病机理。通过研究反应的分子决定因素和对靶向碱的抗性 碱基因重排肺腺癌中的治疗，我们发现致癌碱基因 重排独特而精确地取决于Ras-Raf-Mek-erk（RAS/MAPK）信号 生长和生存。我们的研究表明，依赖性的基础是这种致癌碱 从细胞内的细胞质室而不是脂质膜室中激活RAS 细胞。这是令人惊讶的，因为受体激酶（例如天然ALK和RAS）都在规范上发出信号 仅来自脂质膜室，例如质膜。我们的发现促使 有趣的假设是，RAS信号传导可能来自细胞质中的蛋白颗粒，而不是脂质 某些癌症中的膜室。我们提出了四个利用遗传，蛋白质组学的特定目标 生物物理和细胞生物学研究以检验该假设，目的是首次证明 在有组织的基于蛋白质的结构中，RAS信号传导可以从细胞质中散发的哺乳动物细胞 缺少脂质胶囊。我们最初将在具有致癌碱的肺癌中检验该假设， 扩展到由其他异常激酶基因融合引起的致癌信号传导的人 类似细胞内蛋白质的平台。如果我们的假设是正确的，这些发现将改变我们的 理解癌症的分子基础和推翻25年的教条，该教条持有RAS信号传导 只能从脂质膜室发生。这些发现将对角色产生新的理解 癌症发病机理中的蛋白质颗粒，从而归因于意外的生物学功能 新兴的亚细胞结构类别。我们的努力对设计完全新颖有重要意义 诊断和治疗策略，以利用致病性的疾病 信号传导以改善将来患者的治疗选择。这个项目可能会对 了解癌症发病机理，并为更好地控制癌症的新分子策略铺平了道路。