Fibronectin Contributes to a BRAF Inhibitor-driven Invasive Phenotype in Thyroid Cancer through EGR1, Which Can Be...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• BRAF mutations are prevalent in advanced papillary and anaplastic thyroid cancer (PTC and ATC).
• Current therapies for BRAF-mutant PTC are lacking, and BRAF-mutant ATC patients often experience disease progression despite approved BRAF and MEK1/2 inhibition.
• Thyroid cancer cells resistant to BRAF inhibition (BRAFi) exhibit increased invasion and a proinvasive secretome.

Purpose of the Study:

• To screen BRAF-mutant thyroid cancer cell lines for novel therapeutic strategies.
• To identify mechanisms of resistance to BRAF inhibition in thyroid cancer.
• To evaluate the efficacy of targeting ERK1/2 in combination with BRAF inhibition.

Main Methods:

• Screening of BRAF-mutant thyroid cancer cell lines.
• Reverse-phase protein array (RPPA) analysis to assess protein expression.
• Fibronectin depletion and addition experiments.
• ERK1/2 inhibition studies.
• Patient-derived xenograft (PDX) models.
• RNA sequencing.

Main Results:

• BRAFi treatment led to increased fibronectin expression and secretion in resistant thyroid cancer cells.
• Exogenous fibronectin mimicked BRAFi-induced invasion, while fibronectin depletion abolished it.
• BRAFi-induced invasion was blocked by ERK1/2 inhibition.
• Dual BRAF and ERK1/2 inhibition slowed tumor growth and reduced circulating fibronectin in a PDX model.
• EGR1 was identified as a key mediator of BRAFi-induced invasion and fibronectin induction.

Conclusions:

• Increased invasion is a novel mechanism of resistance to BRAF inhibition in thyroid cancer.
• Combined BRAF and ERK1/2 inhibition represents a promising therapeutic strategy for BRAF-mutant thyroid cancers, particularly those resistant to BRAFi.
• Targeting ERK1/2 can overcome resistance to BRAF inhibitors by inhibiting invasion and fibronectin induction.