Mechanisms of PAK1 activation, signaling and tumor resistance

PAK1 激活、信号转导和肿瘤抵抗的机制

基本信息

批准号：
8639302
负责人：
CHANNING J. DER
金额：
$ 37.07万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/8639302
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 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 public health relevance research clinical testing resistance mechanism sensor small molecule therapeutic target tool tumor

项目摘要

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）：最近的胰腺导管腺癌 (PDAC) 外显子组测序确定，除了 KRAS 近 100% 的突变激活之外，没有其他癌蛋白的突变激活百分比超过个位数。这重新激起了人们对将“不可成药”的 K-Ras 变为可成药的努力的兴趣。最有前途的方向涉及 K-Ras 效应信号传导抑制剂，促使当前的临床评估 Raf-MEK-ERK 级联和磷脂酰肌醇 3-激酶 (PI3K)-AKT-mTOR 信号网络。然而，迄今为止，当作为单一疗法或有限的联合疗法应用时，这些抑制剂对 RAS 突变癌症几乎没有显示出临床疗效。有两个关键问题导致了这次失败。首先，激酶组重编程机制驱动耐药机制，重新激活抑制剂阻断点下游的通路。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 PI3K 效应器，这促使人们努力验证非典型效应器以发现抗 K-Ras 药物。我们建议，针对研究较少的 Rac 小 GTP 酶效应途径及其关键效应物 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，我们建议应用三种创新工具来探究 Rac-PAK 效应网络在 K-Ras 驱动的癌症生长中的作用和机制。具体来说，我们的研究将重点关注信号转导靶向治疗中的两个新兴主题：（i）驱动从头或获得性耐药以限制信号抑制剂治疗活性的动态信号重编程机制，以及（ii）信号蛋白的癌症驱动功能强烈依赖于亚细胞位置。我们组建了一支具有多元化和互补专业知识的研究人员团队，以 (1) 定义异常 K-Ras-Rac1 信号传导激活 PAK1 的机制以及质膜相关、细胞质和核 PAK1 的驱动功能，(2) 确定时空磷酸化事件对于异常 PAK1 激活和 PAK1 依赖性癌症生长至关重要，(3) 分析激酶组重编程，以确定克服 PAK1 抑制以促进(4) 确定 I 组 PAK 抑制是否会增强 PDAC 对 Raf 或 PI3K 效应途径抑制剂的敏感性。