# The Regulation of Apoptosis by Cooperative Src and MAPK Signaling in Thyroid Cancer

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2021 · $38,872

## Abstract

Project Summary/Abstract:
Advanced thyroid cancer patients continue to have dismal prognosis and poor survival ratees due to lack of
effective therapies. While the MAPK pathway accounts for a majority of the mutations that arise in thyroid
cancer (BRAF, RAS, RET/PTC), targeting this pathway has had mixed success in the clinic. The recent
approval of a BRAF inhibitor in combination with a MEK1/2 inhibitor for anaplastic thyroid cancer patients
(ATC) with a BRAF V600E mutation is monumental, however, this combination is only effective in subset of
ATC patients, and is ineffective in BRAF-mutant papillary thyroid cancer (PTC) patients; highlighting the
necessity to identify new therapeutic strategies for patients who do not respond to current therapies. Our lab
has discovered Src as a clinically relevant target in thyroid cancer and we have demonstrated that Src
inhibition with two structurally independent Src inhibitors, dasatinib and saracatinib, inhibits growth, invasion,
and metastasis. However, like many single-agent targeted therapies, clinical responses to single-agent Src
inhibition has been limited in solid tumors, indicating combination therapies will be necessary. Accordingly,
recent studies have shown that the Src inhibitor, dasatinib, in combination with chemotherapeutic agents has
clinical benefit, thus supporting the rationale to identify targets that can be co-inhibited with Src. To this end,
our lab has demonstrated that co-inhibition of Src and MEK1/2 synergizes to inhibit growth, increase survival,
and induce apoptosis in BRAF- and RAS-mutant thyroid cancer cells, while PIK3CA-mutant cells were shown
to be resistant to this combination. To begin to decipher mechanism(s) mediating sensitivity in response to
combined Src and MEK1/2 inhibition, I used a reverse phase protein array (RPPA) of >400 proteins and
phosphoproteins and identified the pro-apoptotic protein, BIM, as a potential mediator of response. Therefore,
the goals of my proposal are to determine the regulation of apoptosis by cooperative Src and MAPK signaling
in thyroid cancer. Specifically, in Aim 1 I will determine the regulation and role of PI3K/AKT-dependent
signaling in mediating the apoptotic response, in Aim 2 I will determine the mechanism(s) of apoptosis
regulated by Src and MAPK signaling, and finally in Aim 3, I will determine the role of combined Src and
MEK1/2 inhibition on tumor growth, metastasis, and the induction of apoptosis in vivo. This proposal
emphasizes a molecular understanding of mechanisms mediating response to Src and MEK1/2 inhibition to
develop new strategies to enhance these effects and potential approaches to sensitize resistant tumors. The
completion of the proposed research will help the National Cancer Institute fulfill their mission to support
cancer research and training in the fundamental sciences.

## Key facts

- **NIH application ID:** 10092807
- **Project number:** 5F31CA247211-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Madison Mariah King Rose
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,872
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092807

## Citation

> US National Institutes of Health, RePORTER application 10092807, The Regulation of Apoptosis by Cooperative Src and MAPK Signaling in Thyroid Cancer (5F31CA247211-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10092807. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*