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.

Public Health Relevance

There are currently no effective therapies for patients with advanced thyroid cancer, especially those with distant metastases. We have shown the Focal Adhesion Kinase (FAK)-Src pathway plays a central role in promoting the aggressive features of thyroid cancer, especially invasion and metastasis. The goals of this proposal are to determine the cooperation between FAK kinase and Src signaling, which will provide important information on how this pathway should be targeted in the clinic for thyroid and other advanced cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA222299-01A1
Application #
9594390
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Chen, Weiwei
Project Start
2018-07-01
Project End
2023-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045