Novel small molecule inhibitors of MEK5_ERK5 for the treatment of breast cancer

项目总结/摘要 丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3-激酶（PI 3 K）的调节异常 通路与乳腺癌病理学有关。MEK 1/2-ERK 1/2 MAPK的激活和 乳腺癌中的PI 3 K/Akt级联增加细胞增殖并维持肿瘤存活。此外，互动 这些途径之间的相互作用与化疗耐药性有关，这表明这些途径的双重抑制 可能是预防乳腺癌生长和转移所必需的。的最新成员 MAPK激酶家族，即MEK 5-ERK 5通路，已被证明能增强癌细胞的生长， 增加患者死亡率。更具体地说，ERK 5激活增加与降低的 乳腺癌患者的无病生存率和与PI 3 K通路的信号串扰已经被 在其他癌症模型中得到证实。使用靶向MEK 1/2-ERK 1/2通路的疗法 PI 3 K/Akt通路的抑制剂处于乳腺癌的I期和II期临床试验中。而 目前有3种MEK 5-ERK 5信号传导的小分子抑制剂， 在乳腺癌模型中进行了测试。此外，在一些乳腺癌细胞中，这些抑制剂对乳腺癌细胞没有特异性。 MEK 5-ERK 5通路，在某些情况下，甚至增加ERK 5活化。因此需要 对于MEK 5-ERK 5通路特异性的新型小分子抑制剂， 可单独使用或与其它激酶抑制剂组合使用。该提案的目标是测试小 我们在体外和体内乳腺癌模型中开发的MEK 5分子抑制剂， 这些新的抑制剂和生物化学方法来检查MEK 5-ERK 5和 乳腺癌中PI 3 K/Akt信号通路的研究因此，本提案的目的是检验以下假设： 新的MEK 5-ERK 5小分子抑制剂减少肿瘤发生、迁移和转移， 增强PI 3 K/Akt抑制剂在乳腺癌中的抗增殖作用。乳腺癌细胞系， 将采用不同的激素分布，并将使用乳腺癌异种移植小鼠模型， 检查MEK 5抑制剂对乳腺肿瘤进展和转移的影响。实验 本申请中提出的方法将提供对MEK 5-ERK 5途径的更深入的机理理解， 这可能导致开发用于乳腺癌患者的新型靶向治疗剂。此外，本发明还 对MEK 5-ERK 5通路的更全面的理解可能对以下方面具有广泛的意义： 各种癌症类型，增加了该提案的重要性。这些目标也将提供一个激励 为本科生和研究生提供培训机会，积极参与研究， 发现过程，以提高我们对癌症生物学中信号转导的理解。

Project Summary/Abstract Dyregulation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositide-3-kinase (PI3K) pathways has been implicated in breast cancer pathology. Activation of the MEK1/2-ERK1/2 MAPK and the PI3K/Akt cascades in breast cancer increases cell proliferation and sustains tumor survival. Further, interaction between these pathways has been implicated in chemoresistance, suggesting that dual inhibition of these pathways may be necessary to prevent breast cancer growth and metastasis. The newest member of the MAPK family of kinases, the MEK5-ERK5 pathway, has been shown to enhance cancer cell growth and increase patient mortality. More specifically, increased ERK5 activation has been associated with decreased disease-free survival in breast cancer patients and signaling crosstalk with the PI3K pathway has been demonstrated in other cancer models. Therapies that target the MEK1/2-ERK1/2 pathways are used clinically and inhibitors of the PI3K/Akt pathway are in Phase I and II clinical trials for breast cancer. While there are currently 3 small molecule inhibitors of MEK5-ERK5 signaling available only one has been tested in breast cancer models. Moreover, in some breast cancer cells, these inhibitors are not specific for the MEK5-ERK5 pathway and, in some cases, even increase ERK5 activation. Therefore, there is a need for novel small molecule inhibitors that are specific for the MEK5-ERK5 pathway that may be clinically useful alone or in combination with other kinase inhibitors. The goal of this proposal is to test small molecule inhibitors of MEK5 that we developed in in vitro and in vivo breast cancer models and to use these novel inhibitors and biochemical methods to examine crosstalk between the MEK5-ERK5 and PI3K/Akt pathways in breast carcinoma. Therefore, the aims of this proposal seek to test the hypothesis that novel small molecule inhibitors of MEK5-ERK5 decrease tumorigenesis, migration, and metastasis and enhance the anti-proliferative effects of PI3K/Akt inhibitors in breast cancer. Breast cancer cell lines with distinct hormonal profiles will be employed and a breast cancer-xenograph mouse model will be used to examine the effect of the MEK5 inhibitors on breast tumor progression and metastasis. The experiments proposed in this application will provide a greater mechanistic understanding of the MEK5-ERK5 pathway, potentially leading to the development of novel, targeted therapeutics for breast cancer patients. Further, a more comprehensive understanding of the MEK5-ERK5 pathway may have widespread implications for various cancer types, adding to the significance of the proposal. These aims will also provide a stimulating training opportunity for undergraduate and graduate students to actively participate in the research and discovery processes to improve our understanding of signal transduction in cancer biology.