Evidence map›Paper›PMID 41501927›Full record

ArticleJournal of experimental & clinical cancer research : CR2026

Dual targeting of BRAF

Jiangnan Hu, Chandrayee Ghosh, Tejinder P Khaket, Zhongyue Yang, Yasmine Tabdili, Eden D Alamaw, Myriem Boufraqech, Scott J Dixon, Electron Kebebew

Abstract read
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In one paragraph

Article in Journal of experimental & clinical cancer research : CR, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Review
  2. Review
  3. Review
  4. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors.

Jiangnan HuDepartment of Surgery, Stanford University, Stanford, CA, USA. johu@stanford.edu.
Chandrayee GhoshDepartment of Surgery, Stanford University, Stanford, CA, USA.
Tejinder P KhaketDepartment of Surgery, Stanford University, Stanford, CA, USA.
Zhongyue YangDepartment of Surgery, Stanford University, Stanford, CA, USA.
Yasmine TabdiliUniversity of Arizona College of Medicine, Tucson, AZ, USA.
Eden D AlamawDepartment of Comparative Medicine, Stanford University, Palo Alto, CA, USA.
Myriem BoufraqechCenter for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
Scott J DixonDepartment of Biology, Stanford University, Stanford, CA, USA.
Electron KebebewDepartment of Surgery, Stanford University, Stanford, CA, USA. kebebew@stanford.edu.

Funding

Characterizing the Regulation of FerroptosisR01GM122923 · NIGMS · STANFORD UNIVERSITY · PI Scott Dixon · 2017 to 2026
$3.4M
Targeting Ferroptosis in BRAF (V600E) Mutant Anaplastic Thyroid CancerR21CA273495 · NCI · STANFORD UNIVERSITY · PI KEBEBEW, ELECTRON · 2023 to 2024
$402k
National Institutes of Health grant R01GM122923NCI NIH HHS 5R21CA273495-02NCI NIH HHS R21 CA273495NIGMS NIH HHS R01 GM122923
6 · The paper itself

Abstract

backgroundWhile combination BRAF and MEK inhibitor treatment in BRAFV600E-mutant cancers results in a response, treatment resistance and toxicity are common. Ferroptosis is an iron-dependent form of non-apoptotic cell death. BRAF inhibition has been associated with increased sensitivity to ferroptosis that is dependent on Glutathione Peroxidase 4 (GPX4).

methodsIn vitro, ex vivo, and in vivo models of anaplastic thyroid cancer (ATC) were used to evaluate the anticancer activity of combination BRAF inhibition and ferroptosis induction.

resultsTargeting key regulators of ferroptosis—GPX4, using RSL3 and ML162, and system Xc−, using erastin—induced significant cell death in all ATC cell lines. Combination of dabrafenib and RSL3 synergistically increased cell death in BRAFV600E-mutant ATC cells, and significantly inhibited colony formation. Mechanistically, lipid peroxidation, reactive oxygen species levels, and intracellular Fe2+ increased significantly with combination treatment compared with each agent alone. Analysis of cell membrane iron importers and exporters showed significantly lower expression of ferroportin-1 (an iron exporter), suggesting the synergistic anticancer activity was due to increased iron accumulation and oxidative stress, leading to enhanced ferroptotic cell death. BRAFV600E-mutant ATC cell spheroids showed synergistic cell death with dabrafenib and RSL3 treatment. In vivo, combination dabrafenib and ferroptosis induction (by targeting GPX4 using C18, and system Xc− with IKE) significantly inhibited tumor growth in an orthotopic ATC mouse model. Additionally, dabrafenib-resistant BRAFV600E-mutant ATC cells were more sensitive to ferroptosis induction than parental cells.

conclusionsDual targeting of BRAFV600E and ferroptosis results in synergistic anticancer activity and overcomes resistance to BRAF inhibition.

Indexed as

FerroptosisOxidative StressProto-Oncogene Proteins B-rafThyroid Carcinoma, AnaplasticAnimalsCarbolinesCell Line, TumorDrug SynergismHumansImidazolesIronMiceMutationOximesXenograft Model Antitumor AssaysBRAF protein, humanCarbolinesdabrafenibImidazolesIronOximesProto-Oncogene Proteins B-rafRSL3 compoundAnaplastic thyroid cancerBRAF mutationCombination therapyFerroptosisGPX4

Identifiers

PMID41501927
PMCPMC12871017

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.