# Targeting Ferroptosis in BRAF (V600E) Mutant Anaplastic Thyroid Cancer

> **NIH NIH R21** · STANFORD UNIVERSITY · 2024 · $178,238

## Abstract

PROJECT SUMMARY/ABSTRACT
BRAFV600E mutations are common in anaplastic thyroid cancer (ATC, 50-75% positive), which is refractory to
standard treatment and has high mortality rates. Monotherapy with BRAF inhibitors is ineffective in patients
with BRAFV600E-mutant ATC. Although, combination therapy using a BRAF inhibitor, and a mitogen-activated
protein kinase (MEK) inhibitor is more effective than BRAF inhibitor monotherapy, acquired resistance is
common because BRAF and MEK act on the same downstream target and largely the same pathway. A
feature of resistance to BRAF inhibition or combined BRAF and MEK inhibition is increased sensitivity to
agents that induce ferroptosis (a distinct mechanism of programmed cell death dependent on iron). Moreover,
it has been shown that treatment-resistant (including BRAF inhibitor-resistant) cancer cells (persister cells) are
associated with a mesenchymal state that is dependent on GPX4 (a gatekeeper and suppressor of ferroptosis)
and show increased sensitivity to ferroptosis induction. Our unpublished preliminary data show that ferroptosis
induction is more pronounced in BRAFV600E-mutant than wild type ATC cells and that combination BRAF
inhibition and ferroptosis induction has synergistic activity in causing cell death in BRAFV600E-mutant ATC cells.
The long-term goal is the development of novel science-based treatment strategies for ATC that improve
patient outcomes. The overall objective in this application is to determine the safety and preclinical therapeutic
efficacy of combined BRAF inhibitor and ferroptosis induction treatment in BRAFV600E-mutant ATC. The central
hypothesis in this proposal is that combination therapy with BRAF inhibitor and ferroptosis induction will have
synergistic/additive anti-cancer activity in BRAFV600E-mutant ATC. The rationale for this project is that
determination of the safety and preclinical therapeutic efficacy of ferroptosis induction with BRAF inhibition is
likely to offer a strong scientific basis for translation of this novel combinatorial treatment strategy to the clinic.
The central hypothesis will be tested by pursuing two specific aims: 1) Evaluate the safety and anticancer
activity of targeting ferroptosis in combination with BRAF inhibition in BRAFV600E-mutant ATC in vitro and in
vivo; and 2) Evaluate the efficacy of combined ferroptosis induction and BRAF inhibition compared to
combination BRAF and MEK inhibition. The research proposed in this application is innovative, in the
applicant’s opinion, as it represents a significant departure from the current strategy of targeting BRAF only or
a single signaling pathway in BRAFV600E-mutant ATC to the concept that combined treatment with a BRAF
inhibitor and ferroptosis induction will result in more robust and synergistic/additive anticancer activity. The
proposed research is significant because it is expected to provide a strong scientific justification for future
studies that could provide a new mechanism-based treat...

## Key facts

- **NIH application ID:** 10877833
- **Project number:** 5R21CA273495-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Electron Kebebew
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $178,238
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877833

## Citation

> US National Institutes of Health, RePORTER application 10877833, Targeting Ferroptosis in BRAF (V600E) Mutant Anaplastic Thyroid Cancer (5R21CA273495-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10877833. Licensed CC0.

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