Role of the ETV5/p38 Signaling Axis in Aggressive Thyroid Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have poor prognoses.
• BRAFV600E mutation activates MAPK, driving cancer growth, but resistance to inhibitors develops.
• ETV5 expression is linked to BRAFV600E in PDTC/ATC, suggesting a role in pathway activation.

Purpose of the Study:

• Investigate the link between ETV5, p38, and MAPK pathways in aggressive thyroid cancers.
• Evaluate the efficacy of combining p38 inhibitors with BRAF inhibitor dabrafenib.
• Explore therapeutic strategies to overcome resistance in PDTC and ATC.

Main Methods:

• Analyzed ETV5 expression and its association with p38 pathway activation.
• Reduced ETV5 levels to assess impact on p38 and upstream regulators (MKK3/MKK6).
• Performed high-throughput screening of p38 inhibitors combined with dabrafenib in vitro and in a mouse model.

Main Results:

• ETV5 expression correlates with p38 activation; reducing ETV5 decreases p38 signaling.
• Combined p38 and BRAF inhibition shows strong synergy, overcoming resistance in TP53-mutated cells.
• Combination therapy demonstrated efficacy in a preclinical mouse model of ATC.

Conclusions:

• The MAPK and p38/MAPK14 pathways are interconnected and oncogenic in aggressive thyroid cancers.
• Combining p38 inhibitors with dabrafenib offers a potential therapeutic strategy for PDTC and ATC.
• Development of more specific p38 inhibitors is needed to maximize treatment benefits.