BRAF Signaling in Thyroid Cancer

Papillary thyroid cancer (PTC) is the most common endocrine malignancy, with a rising global incidence and particularly high prevalence among Saudi women, where it ranks as the second most common cancer after breast cancer. Although most PTC cases are indolent, 10–15% exhibit aggressive behavior with resistance to standard therapies, leading to poor clinical outcomes. The BRAFV600E mutation, present in 60–80% of PTCs, is a key driver of tumor progression through constitutive MAPK pathway activation, promoting proliferation, dedifferentiation, and resistance to apoptosis. Despite advances, the complexity of BRAF-driven signaling and its downstream regulators remains incompletely understood.

Our RNA-seq analysis identified 508 genes upregulated in BRAFV600E-mutant PTC cells, of which 27 were downregulated following BRAF inhibitor treatment, suggesting their involvement in BRAF-mediated oncogenesis. This project aims to investigate the functional and prognostic roles of these candidate genes in PTC progression using a comprehensive approach integrating clinical tissue microarrays, PTC cell lines, pharmacological inhibition, gene manipulation, and xenograft models.

By characterizing novel regulators within the BRAF signaling cascade, this study will provide insights into molecular mechanisms underlying aggressive PTC and identify potential biomarkers and therapeutic targets. The findings are expected to advance precision oncology and improve treatment strategies for Saudi patients with resistant PTC.