Fibronectin Contributes to a Braf Inhibitor-Driven Invasive Phenotype in Thyroid Cancer Through EGR1, Which Can Be Blocked by Inhibition of ERK1/2

Authors

Hannah M Hicks
Nikita Pozdeyev
Sharon B Sams
Umarani Pugazhenthi
Elise S Bales
Marie-Claude Hofmann
Logan R McKenna
Rebecca E Schweppe

Publication Date

9-1-2023

Journal

Molecular Cancer Research

Abstract

Mutations in BRAF are common in advanced papillary and anaplastic thyroid cancer (PTC and ATC). However, patients with BRAF-mutant PTC currently lack therapies targeting this pathway. Despite the approved combination of BRAF and MEK1/2 inhibition for patients with BRAF-mutant ATC, these patients often progress. Thus, we screened a panel of BRAF-mutant thyroid cancer cell lines to identify new therapeutic strategies. We showed that thyroid cancer cells resistant to BRAF inhibition (BRAFi) exhibit an increase in invasion and a proinvasive secretome in response to BRAFi. Using reverse-phase protein array (RPPA), we identified a nearly 2-fold increase in expression of the extracellular matrix protein, fibronectin, in response to BRAFi treatment, and a corresponding 1.8- to 3.0-fold increase in fibronectin secretion. Accordingly, the addition of exogenous fibronectin phenocopied the BRAFi-induced increase in invasion while depletion of fibronectin in resistant cells resulted in loss of increased invasion. We further showed that BRAFi-induced invasion can be blocked by inhibition of ERK1/2. In a BRAFi-resistant patient-derived xenograft model, we found that dual inhibition of BRAF and ERK1/2 slowed tumor growth and decreased circulating fibronectin. Using RNA sequencing, we identified EGR1 as a top downregulated gene in response to combined BRAF/ERK1/2 inhibition, and we further showed that EGR1 is necessary for a BRAFi-induced increase in invasion and for induction of fibronectin in response to BRAFi.

Implications: Together, these data show that increased invasion represents a new mechanism of resistance to BRAF inhibition in thyroid cancer that can be targeted with an ERK1/2 inhibitor.

Keywords

Humans, MAP Kinase Signaling System, Fibronectins, Proto-Oncogene Proteins B-raf, Protein Kinase Inhibitors, Thyroid Neoplasms, Thyroid Cancer, Papillary, Phenotype, Early Growth Response Protein 1

Comments

Trial registration: ClinicalTrials.gov NCT02034110 NCT01723202.

Supplementary Materials

PMID: 37219859