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: 8998934
• 负责人: CHANNING J. DER
• 金额: $ 42.43万
• 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/8998934
• 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; FRAP1 gene; 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; Oncogenes; 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; 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）：胰腺导管腺癌（PDAC）最近的外显子组测序确定，除了KRAS接近100％突变激活外，没有其他癌蛋白是超出单位数字百分比的突变激活的。这对使“不可能”的K-Ras可吸毒的努力重新引起了兴趣。最有希望的方向涉及K-RAS效应子信号传导的抑制剂 Raf-Mekerk级联反应和磷脂酰肌醇3-激酶（PI3K）-Akt-MTOR信号网络。但是，迄今为止，当作为单一疗法或有限的组合方法应用时，这些抑制剂对RAS突变癌的临床功效几乎没有。两个关键问题导致了这一失败。首先，Kinome重编程机制驱动了电阻机制，该机制将抑制剂块点下游的途径重新激活。其次，很明显，癌细胞对突变体K-RAS的依赖性不能仅归因于RAF和PI3K效应子，从而促进了为验证抗K-RAS药物发现的非规范效应子的努力。我们建议对较小的RAC小型GTPase效应途径及其关键效应子进行治疗靶向，I PAK丝氨酸/苏氨酸激酶将解决这两个问题。为此，我们提出了三种创新工具来询问RAC-PAK效应网络对K-RAS驱动的癌症增长的作用和机制的应用。具体而言，我们的研究将集中在信号转导靶向疗法中的两个沉浸主题上：（i）动态信号重编程机制，这些机制驱动从头开始或获得抗性以限制信号抑制剂的治疗活性，并且（ii）信号蛋白的癌症驱动因素对亚细胞位置非常依赖。 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重编程以鉴定克服PAK1抑制以促进癌细胞耐药性的补偿性蛋白激酶，并且（4）确定I组抑制是否会增强对RAF或PI3K效应途径抑制剂的PDAC敏感性。