Mechanisms of PAK1 activation, signaling and tumor resistance

PAK1 激活、信号转导和肿瘤抵抗的机制

• 批准号: 8800547
• 负责人: CHANNING J. DER
• 金额: $ 36.19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-05 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800547
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Apoptotic; Automobile Driving; BRAF gene; Binding; Biological; Bypass; Cancer Etiology; Cell Culture Techniques; Cell Death; Cell membrane; Cessation of life; Clinical; Collection; Complex; Computer Simulation; Conflict (Psychology); Dependency; Development; Digit structure; Drug Targeting; Drug resistance; Employee Strikes; Event; Failure; Feedback; Growth; Health; KRAS2 gene; Location; MAP2K1 gene; MEKs; Malignant Neoplasms; Malignant neoplasm of pancreas; Mitochondria; Mitogen-Activated Protein Kinases; Monomeric GTP-Binding Proteins; Mutate; Nature; Nuclear; Oncogene Proteins; Output; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phosphatidylethanolamine Binding Protein; Phosphorylation; Phosphotransferases; Protein Kinase; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Research Personnel; Resistance; Role; Route; Signal Transduction; Signaling Protein; Skin Neoplasms; Staging; Therapeutic; Tumor Biology; Validation; cancer cell; cancer therapy; clinical efficacy; design; drug discovery; exome sequencing; human FRAP1 protein; inhibitor/antagonist; innovation; interest; mathematical model; melanoma; mouse model; mutant; pre-clinical; protein kinase inhibitor; research clinical testing; resistance mechanism; sensor; small molecule; targeted treatment; therapeutic target; tool; tumor

DESCRIPTION (provided by applicant): Recent exome sequencing of pancreatic ductal adenocarcinoma (PDAC) determined that aside from the near 100% mutational activation of KRAS, no other oncoproteins are mutationally activated beyond single digit percentages. This has renewed interest in efforts to make "undruggable" K-Ras druggable. The most promising direction involves inhibitors of K-Ras effector signaling, prompting current clinical evaluation of the Raf-MEK- ERK cascade and the phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR signaling network. However, to date, when applied as monotherapy, or with limited combination approaches, these inhibitors have shown little to no clinical efficacy for RAS mutant cancers. Two key issues contribute to this failure. First, kinome reprogramming mechanisms drive resistance mechanisms that reactivate the pathway downstream of the inhibitor block point. Second, it is clear that cancer cell dependency on mutant K-Ras cannot be attributed to the Raf and PI3K effectors alone, prompting efforts to validate noncanonical effectors for anti-K-Ras drug discovery. We propose that therapeutic targeting of the lesser studied Rac small GTPase effector pathway and its key effector, the Group I PAK serine/threonine kinases will address both issues. To accomplish this, we propose the application of three innovative tools to interrogate the role and mechanism by which the Rac-PAK effector network contributes to K-Ras-driven cancer growth. Specifically, our studies will focus on two immerging themes in signal transduction targeted therapies: (i) dynamic signal reprogramming mechanisms that drive de novo or acquired resistance to limit the therapeutic activity of signaling inhibitors and (ii) the cancer driver function of a signaling protein is strongly dependent on subcellular location. We have assembled a team of researchers with diverse and complementary expertise to (1) define the mechanisms of PAK1 activation by aberrant K-Ras- Rac1 signaling and the driver functions of plasma membrane-associated, cytoplasmic and nuclear PAK1, (2) identify the spatio-temporal phosphorylation events essential for aberrant PAK1 activation and PAK1- dependent cancer growth, (3) profile kinome reprogramming to identify the compensatory protein kinases that overcome PAK1 inhibition to promote cancer cell resistance, and (4) determine if Group I PAK suppression enhances PDAC sensitivity to inhibitors of the Raf or PI3K effector pathways.

描述（由申请人提供）：最近对胰腺导管腺癌（PDAC）的外显子组测序确定，除了KRAS的近100%突变激活外，没有其他癌蛋白的突变激活超过个位数百分比。这重新引起了人们对使“不可药用”的K-Ras可药用的努力的兴趣。最有希望的方向涉及K-Ras效应信号传导的抑制剂，促进了目前的临床评估， Raf-MEK- ERK级联和磷脂酰肌醇3-激酶（PI 3 K）-AKT-mTOR信号网络。然而，迄今为止，当作为单药治疗或与有限的组合方法一起应用时，这些抑制剂对RAS突变型癌症几乎没有临床疗效。两个关键问题导致了这一失败。首先，激酶组重编程机制驱动重新激活抑制剂阻断点下游途径的抗性机制。其次，很明显，癌细胞对突变型K-Ras的依赖性不能单独归因于Raf和PI 3 K效应子，这促使人们努力验证用于抗K-Ras药物发现的非经典效应子。我们建议，针对研究较少的Rac小GTPase效应子途径及其关键效应子I组PAK丝氨酸/苏氨酸激酶的治疗靶向将解决这两个问题。为了实现这一目标，我们提出了三种创新工具的应用，以询问Rac-PAK效应器网络有助于K-Ras驱动的癌症生长的作用和机制。具体来说，我们的研究将集中在两个沉浸在信号转导靶向治疗的主题：（i）动态信号重编程机制，驱动从头或获得性耐药性，以限制信号传导抑制剂的治疗活性和（ii）信号传导蛋白的癌症驱动功能强烈依赖于亚细胞位置。我们已经组建了一个具有不同和互补专业知识的研究人员团队，以（1）通过异常K-Ras-Rac 1信号传导和质膜相关，细胞质和细胞核PAK 1的驱动功能来定义PAK 1激活的机制，（2）确定异常PAK 1激活和PAK 1依赖性癌症生长所必需的时空磷酸化事件，（3）分析激酶组重编程以鉴定克服PAK 1抑制以促进癌细胞抗性的补偿性蛋白激酶，和（4）确定组I PAK抑制是否增强PDAC对Raf或PI 3 K效应子途径的抑制剂的敏感性。