Targeting FAK and Src in thyroid cancer

项目总结 目前对晚期甲状腺癌患者的治疗方法很少治愈。甲状腺外侵犯和 转移是甲状腺癌相关死亡的最常见原因，但进展甚微 为这些患者开发新的治疗方法。粘着斑激酶(FAK)与Src激酶 途径已成为癌症进展的主要参与者，特别是与转移有关，但如何源 FAK促进疾病进展，转移过程尚不清楚。我们已经展示了 FAK在患者甲状腺肿瘤样本中过表达和磷酸化，以及对Src的抑制 在体外和体内抑制甲状腺癌的生长和转移。我们已将FAK映射为关键下游 靶基因Src，FAK接头/支架功能，而不是激酶活性，是甲状腺癌的关键 生长和转移。虽然这些数据表明FAK和Src在甲状腺中具有重要的促肿瘤作用 对于癌症，显然，对单剂靶向治疗产生耐药性是不可避免的。至 为了解决这个问题，我们开发了一个对Src抑制剂达沙替尼的获得性耐药性模型， 确定预先联合治疗的靶点的目标。使用这种后天抵抗力模型，我们 已经确定了一种向更具侵袭性的表型的转变，这是由依赖于 FAK适配器/支架作用于FAK激酶活性，可能受c-Met-FAK复合体调节， 导致对p130Cas和c-jun信号轴的依赖增加。我们进一步表明，这更多地 侵袭性表型伴随着分泌体和金属蛋白酶活性的改变，而IL-1β 而基质金属蛋白酶在这一反应中起着关键作用。因此，这项建议的目标是界定IL- 1β&gt；c-Met-FAK&gt；p130Cas&gt；c-jun&gt；MMP信号轴在甲状腺肿瘤生长和侵袭中的作用 了解FAK作为这种表型转换的中央调节因子的调节和功能。在目标1中，我们将 利用遗传学和药理学方法确定FAK和Src抑制的协同作用机制 P130Cas&gt；c-jun信号模块的作用。在目标2中，我们将定义FAK在调解更多 侵袭性表型，以及IL-1β和MMPs在此反应中的作用。在目标3中，我们将研究c- MET调节FAK功能，并使用体内原位甲状腺癌模型和实验性甲状腺癌 转移模型，以确定FAK作为体内靶点与Src抑制相结合的作用。成功 这些目标的完成将定义FAK作为响应Src指令的分子开关的角色 治疗，以及对更具侵袭性的表型的调节。总体而言，这些研究将确定 FAK和Src作为晚期甲状腺癌治疗靶点及预防 转移癌，以及其他带有致癌FAK和Src信号的低分化癌症。

PROJECT SUMMARY Current therapies for patients with advanced thyroid cancer are rarely curative. Extrathyroidal invasion and metastasis are the most common causes of thyroid cancer-related deaths, and little progress has been made in the development of new therapies for these patients. The Focal Adhesion Kinase (FAK) and Src kinase pathway has emerged as a major player in cancer progression, especially relating to metastasis, yet how Src and FAK promote disease progression and the metastatic process is not well understood. We have shown that FAK is overexpressed and phosphorylated in patient thyroid tumor samples, and that inhibition of Src inhibits thyroid cancer growth and metastasis in vitro and in vivo. We have mapped FAK as a key downstream target of Src, and that the FAK adaptor/scaffolding function, but not kinase activity, is critical for thyroid cancer growth and metastasis. While these data demonstrate a major pro-tumorigenic role for FAK and Src in thyroid cancer, it is clear that the development of resistance to single-agent targeted therapies is inevitable. To address this problem, we have developed a model of acquired resistance to the Src inhibitor, dasatinib, with the goal of identifying targets for upfront combination therapies. Using this model of acquired resistance, we have identified a switch to a more invasive phenotype, which is driven by a key switch in dependency from FAK adaptor/scaffolding function to FAK kinase activity, which may regulated by a c-Met-FAK complex, resulting in an increased reliance on the p130Cas>c-Jun signaling axis. We have further shown that this more invasive phenotype is accompanied by an altered secretome and metalloprotease activity, and that IL-1beta and MMP play key roles in this response. Thus, the goals of this proposal are to define the role of the IL- 1beta>c-Met-FAK>p130Cas>c-Jun>MMP signaling axis in thyroid tumor growth and invasion, and to understand the regulation and function of FAK as a central mediator of this phenotype switch. In Aim 1 we will use genetic and pharmacologic approaches to define the mechanism of synergy of FAK and Src inhibition and the role of the p130Cas>c-Jun signaling module. In Aim 2, we will define the role of FAK in mediating a more invasive phenotype, and the role of IL-1beta and MMPs in this response. In Aim 3, we will investigate how c- Met regulates FAK function, and use an in vivo orthotopic thyroid cancer model and an experimental metastasis model to define the role of FAK as an in vivo target in combination with Src inhibition. Successful completion of these aims will define the role of FAK as a molecular switch in response to Src-directed therapies, and in the regulation of a more invasive phenotype. Overall, these studies will determine the role of FAK and Src as therapeutic targets for patients with advanced thyroid cancer, and the prevention of metastases, as well as other poorly differentiated cancers with oncogenic FAK and Src signaling.