β-Catenin Attenuation Inhibits Tumor Growth and Promotes Differentiation in a BRAFV600E-Driven Thyroid Cancer Animal Model

BRAF(V600E) mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). b-Catenin (Ctnnb1) is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. BRAF(V600E)- driven tumors have been speculated to rely on Wnt/beta-catenin signaling to sustain its growth, although many details remain to be elucidated. In this study, we investigated the role of beta-catenin in Braf(V600E)-driven thyroid cancer in a transgenic mouse model. In Braf(V600E) mice with wild-type (WT) Ctnnb1 (BVE-Ctnnb1(WT) or BVE), overexpression of beta-catenin was observed in thyroid tumors. In Braf(V600E) mice with Ctnnb1 knockout (BVE-Ctnnb1(null)), thyroid tumor growth was slowed with significant reduction in papillary architecture. This was associated with increased expression of genes involved in thyroid hormone synthesis, elevated (124)iodine uptake, and serum T4. The survival of BVE-Ctnnb1null mice was increased by more than 50% during 14-month observation. Mechanistically, downregulation of MAPK, PI3K/Akt, and TGF beta pathways and loss of epithelial-mesenchymal transition (EMT) were demonstrated in the BVE-Ctnnb1(null) tumors. Treatment with dual beta-catenin/KDM4A inhibitor PKF118-310 dramatically improved the sensitivity of BVE-Ctnnb1(WT) tumor cells to BRAF(V600E) inhibitor PLX4720, resulting in significant growth arrest and apoptosis in vitro, and tumor regression and differentiation in vivo. These findings indicate that beta-catenin signaling plays an important role in thyroid cancer growth and resistance to BRAF(V600E) inhibitors. Simultaneously targeting both Wnt/beta-catenin and MAPK signaling pathways may achieve better therapeutic outcome in BRAF(V600E) inhibitorresistant and/or radioiodine-refractory thyroid cancer.

Automated summary

The study reveals that beta-catenin signaling is crucial in thyroid cancer growth and resistance to BRAF(V600E) inhibitors. Simultaneously targeting both Wnt/beta-catenin and MAPK signaling pathways may achieve better therapeutic outcome in BRAF(V600E) inhibitor-resistant and/or radioiodine-refractory thyroid cancer.