Role of p21-activated kinases in thyroid cancer

p21 激活激酶在甲状腺癌中的作用

• 批准号: 10377551
• 负责人: Matthew D Ringel
• 金额: $ 36.76万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377551
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; BRAF gene; Binding; Cell Line; Cell Proliferation; Cell division; Cells; Centrosome; Cessation of life; Chronic; Clinic; Complex; Data; Diagnosis; Disease; Distant Metastasis; Gene Expression Profile; Goals; Human; I131 isotope; In Vitro; In complete remission; Indolent; KRAS2 gene; Knock-in; MEK inhibition; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Mediating; Methods; Mitosis; Mitotic Activity; Modeling; Molecular; Mutate; Mutation; Outcome; Papillary thyroid carcinoma; Pathway interactions; Patients; Phosphorylation; Play; Prognosis; Publishing; Ras/Raf; Regulation; Reporting; Research; Resistance; Resistance development; Role; Sampling; Signal Transduction; Signaling Molecule; System; Taxonomy; Testing; Therapeutic; Thyroid Gland; Tissues; Work; base; cancer cell; cell growth; cell motility; improved; in vivo; inducible gene expression; inhibitor; knock-down; melanoma; member; mortality; mouse model; mutant; novel; novel therapeutics; overexpression; p21 activated kinase; p21-activated kinase 1; patient derived xenograft model; protein complex; response; synergism; therapeutic evaluation; therapeutic target; therapy resistant; tumor; tumor progression; tumorigenesis

Patients with progressive metastatic papillary thyroid cancer (PTC) have a poor prognosis. Despite advances in developing new therapies complete responses have been elusive and non-durable responses are the best reported outcomes. The presence of gross local invasion and distant metastases are two predictors of death from PTC. We have focused on defining key regulators of these features in an effort to identify novel targets to improve treatment. We identified that the p21 activated kinase (PAK) signaling is activated in the invasive fronts of aggressive PTCs and determined that it regulated human thyroid cancer cell motility and proliferation in vitro. Because of the association between BRAF activation and tumor aggressiveness we analyzed the relationship between these two signaling molecules. We demonstrated that PAK activity was highly regulated by BRAF and that BRAF knock down inhibited PAK activity. Moreover, this effect was independent of MEK. We subsequently identified that PAK physically interacts with BRAF both overexpression and endogenous systems and that the complex occurs in mitosis consistent with a role in regulation cell division and growth. We have shown in vivo that acute activation of BRAF V600E in the thyroid is associated with increased levels of phosphorylated PAK. Finally, we have identified acquired mutations in upstream regulators of PAK in tumor samples from patients who developed resistance to BRAF inhibition. These data point to PAK being a critical downstream target of BRAF which plays an important functional role in PTC progression for tumors with RAS/RAF/ERK pathway activation. The hypotheses of this project is that PAK is a critical signaling node downstream of BRAF involved in thyroid cancer tumorigenesis and progression in vivo; that the mechanism of the interaction can be elucidated, and that it can be exploited to develop improved primary and secondary therapies for patients with progressive thyroid cancer and other patients with BRAF-mutated tumors.

进行性转移性甲状腺乳头状癌（PTC）患者预后较差。尽管在开发新疗法方面取得了进展，但完全缓解仍然难以捉摸，并且非持久缓解是最好的报告结果。局部大面积浸润和远处转移是 PTC 死亡的两个预测因素。我们专注于定义这些特征的关键调节因子，以期确定改善治疗的新靶点。我们发现 p21 激活激酶 (PAK) 信号在侵袭性 PTC 的侵袭前沿被激活，并确定它在体外调节人甲状腺癌细胞的运动和增殖。由于 BRAF 激活与肿瘤侵袭性之间的关联，我们分析了这两种信号分子之间的关系。我们证明 PAK 活性受到 BRAF 的高度调节，并且 BRAF 敲低会抑制 PAK 活性。此外，这种效应与 MEK 无关。我们随后发现 PAK 与 BRAF 过表达和内源系统发生物理相互作用，并且该复合物发生在有丝分裂中，与调节细胞分裂和生长的作用一致。我们在体内证明，甲状腺中 BRAF V600E 的急性激活与磷酸化 PAK 水平的增加有关。最后，我们在对 BRAF 抑制产生耐药性的患者的肿瘤样本中发现了 PAK 上游调节因子的获得性突变。这些数据表明 PAK 是 BRAF 的关键下游靶点，在 RAS/RAF/ERK 通路激活的肿瘤的 PTC 进展中发挥重要的功能作用。本项目假设PAK是BRAF下游的关键信号节点，参与甲状腺癌体内肿瘤的发生和进展；可以阐明相互作用的机制，并可以利用它为进展性甲状腺癌患者和其他 BRAF 突变肿瘤患者开发改进的主要和次要疗法。