P38, G2 Arrest, and Temozolomide Resistance in Gliomas

描述(申请人提供)：这项研究的长期目标是通过更好地了解对替莫唑胺(TMZ)的敏感性/耐药性的基础来改进胶质瘤的治疗，替莫唑胺是一种在胶质瘤治疗中重要的化疗药物。众所周知，胶质瘤对TMZ的敏感性/耐药性受到TMZ诱导的DNA损伤的程度和肿瘤修复这种损伤的能力的影响。然而，胶质瘤对TMZ的敏感性/耐药性也受到G2细胞周期检查点的影响，该检查点的激活可以将TMZ诱导的DNA损伤与TMZ诱导的细胞毒性分离。TMZ诱导的G2检查点部分由Chk1通路控制，Chk1通路的激活导致CDc2/Cyclin B复合体的磷酸化，G2停滞，并保护其免受TMZ的毒性。我们最近发现的证据表明，涉及p38应激激酶的第二个独立通路也可能控制TMZ诱导的G2停滞，进而控制TMZ的敏感性/耐药性。尽管它在控制TMZ敏感性/耐药性方面具有潜在的重要性，但p38通路的激活和激活的后果，以及它与Chk1通路的相互作用和治疗操作的可能性仍未确定。我们假设：1)DNA错配修复诱导的DNA单链断裂激活了p38通路；2)DNA损伤传感器c-ABL、53BP1、ATM和/或ATR连接MMR对p38激活的DNA损伤；3)激活的p38通过抑制CDC25B和/或cdc25C的核活性而参与启动TMZ诱导的G2细胞停滞；4)p38通过对依赖于p53和p21的CDC2的作用而维持TMZ诱导的G2细胞停滞。 5)抑制p38和Chk1通路将在体外和体内共同或协同地增强胶质瘤细胞对TMZ的敏感性。这些研究的结果有望更好地理解TMZ诱导的G2检查点，并鉴定TMZ诱导的G2检查点，从而在胶质瘤中选择性逆转TMZ耐药性的方式。

DESCRIPTION (provided by applicant): The long-term objective of this study is to improve the therapy of gliomas by better understanding the basis for sensitivity/resistance to temozolomide (TMZ), a chemotherapeutic agent important in the treatment of gliomas. The sensitivity/resistance of gliomas to TMZ is well known to be influenced by the extent of TMZ-induced DNA damage and by the ability of the tumor to repair this damage. The sensitivity/resistance of gliomas to TMZ is also, however, influenced by the G2 cell cycle checkpoint, activation of which can dissociate TMZ-induced DNA damage from TMZ-induced cytotoxicity. The TMZ-induced G2 checkpoint is controlled in part by the Chk1 pathway, activation of which leads to phosphorylation of the Cdc2/Cyclin B complex, G2 arrest, and protection from TMZ toxicity. We recently uncovered evidence that a second independent pathway involving the p38 stress kinases may also control TMZ-induced G2 arrest and, in turn, TMZ sensitivity/resistance. Despite its potential importance in controlling TMZ sensitivity/resistance, the activation and consequences of activation of the p38 pathway, as well as its interaction with the Chk1 pathway and potential for therapeutic manipulation remain undefined. We hypothesize that 1) the p38 pathway is activated following TMZ exposure by DNA mismatch repair-induced DNA single- strand breaks, 2) the DNA damage sensors c-abl, 53BP1, ATM, and/or ATR link MMR-induced DNA damage to p38 activation, 3) activated p38 contributes to the initiation of TMZ-induced G2 arrest by suppressing nuclear activity of Cdc25 B and/or Cdc25C, and Cdc2-cyclin B complexes, 4) p38 contributes to the maintenance of TMZ-induced G2 arrest by effects on p53- and p21-dependent Cdc2 activation, and 5) inhibition of the p38 and Chk1 pathways will additively or synergistically sensitize glioma cells to TMZ in vitro and in vivo. The results of these studies are expected to lead to a better understanding of the TMZ-induced G2 checkpoint and to identification of ways in which the TMZ-induced G2 checkpoint, and hence TMZ resistance, can be selectively reversed in gliomas.