PAK Kinases Regulate Melanoma Chemoresistance and Metastasis

PAK 激酶调节黑色素瘤化疗耐药和转移

基本信息

批准号：
9262324
负责人：
Anand K Ganesan
金额：
$ 9.67万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-07 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262324
关键词：
ATR gene Actins Apoptosis BRAF gene Biological Markers Cell Cycle Arrest Chemotherapy-Oncologic Procedure DNA Damage DNA Double Strand Break Development Diagnostic Neoplasm Staging Effectiveness Event Genes Growth Health Homologous Gene Human In Vitro Individual Invaded Lead Lung Mammary Neoplasms Mediator of activation protein Melanoma Cell Metastatic Melanoma Metastatic Neoplasm to Lymph Nodes Modeling Molecular Mus Mutant Strains Mice Neoplasm Metastasis PAK-1 kinase Pathway interactions Patient Care Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Proteins RNA interference screen Recruitment Activity Resistance Resistance development Site Skin Neoplasms Staging System Tissues Tumor stage Work Xenograft Model Xenograft procedure cancer cell chemotherapy cohort conventional therapy design improved in vivo inhibitor/antagonist innovation melanoma migration mutant outcome forecast prevent response tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Melanoma tumors metastasize at an early stage of development and are notoriously resistant to chemotherapeutics. We recently utilized a systems-level RNAi screening approach to uncover the molecular regulators of melanoma chemoresistance. These studies determined that RhoJ and its downstream kinase PAK1 suppress pathways in melanoma cells that sense DNA damage. Additional studies revealed that RhoJ and PAK1 also regulate melanoma invasion by modulating actin cytoskeletal dynamics. These observations led us to hypothesize that PAK kinases phosphorylate downstream targets that suppress DNA damage sensing and promote melanoma metastasis. In this proposal, we determine how PAK1 suppresses DNA damage sensing and determine whether Pak1 suppresses DNA damage sensing in vivo. Additional studies will identify PAK kinase targets that modulate melanoma cell invasion and verify that PAK kinases regulate melanoma metastasis in vivo. In the final aim of the proposal, we will examine whether PAK kinases are selectively activated in poor prognosis/chemoresistant human melanomas and determine whether PAK inhibitors can both sensitize mouse melanomas to chemotherapeutics and inhibit murine melanoma metastasis. Completion of these studies will lead to the design of more effective PAK inhibitors that can be used to treat metastatic melanoma.

描述（由申请人提供）：黑色素瘤在发育的早期阶段转移，众所周知对化学治疗性具有抗药性。我们最近利用了系统级RNAi筛选方法来揭示黑色素瘤化学耐药性的分子调节剂。这些研究确定Rhoj及其下游激酶PAK1抑制了具有DNA损伤的黑色素瘤细胞中的途径。其他研究表明，Rhoj和Pak1还通过调节肌动蛋白细胞骨架动力学来调节黑色素瘤侵袭。这些观察结果导致我们假设PAK激酶磷酸化的下游靶标可抑制DNA损伤感应并促进黑色素瘤转移。在此提案中，我们确定PAK1如何抑制DNA损伤感应并确定PAK1是否抑制了体内DNA损伤感应。其他研究将确定调节黑色素瘤细胞侵袭的PAK激酶靶标，并验证PAK激酶在体内调节黑色素瘤转移。在该提案的最终目的中，我们将检查PAK激酶是否在预后不良/化学耐药的人黑色素瘤中是否有选择地激活，并确定PAK抑制剂是否可以使小鼠黑色素瘤对化学疗法敏感并抑制鼠类黑色素瘤转移。这些研究的完成将导致设计更有效的PAK抑制剂，可用于治疗转移性黑色素瘤。