# Targeting FAK and Src in thyroid cancer

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $520,597

## Abstract

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.

## Key facts

- **NIH application ID:** 10454792
- **Project number:** 5R01CA222299-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Rebecca Elizabeth Schweppe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $520,597
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454792

## Citation

> US National Institutes of Health, RePORTER application 10454792, Targeting FAK and Src in thyroid cancer (5R01CA222299-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10454792. Licensed CC0.

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