Upregulation of TRIB2 by Wnt/β-catenin activation in BRAFV600E papillary thyroid carcinoma cells confers resistance to BRAF inhibitor vemurafenib

Purpose The BRAF(V600E) mutation is an oncogenic driver associated with aggressive tumor behaviors and increased mortality among patients with papillary thyroid cancer (PTC). Although the BRAF inhibitor vemurafenib gave promising results in BRAF(V600E)-mutant PTC, resistance development remains a major clinical challenge. This study aimed to explore the mechanisms underlying drug resistance in PTC. Methods Two vemurafenib-resistant PTC cell lines (KTC1 and BCPAP) were established by continuous treatment with vemurafenib for 5 months. The knockdown and upregulation of Tribbles homolog 2 (TRIB2) in PTC cells were achieved by the transfection with short hairpin RNA against TRIB2 or recombinant lentiviral vector carrying TRIB2, respectively. The beta-catenin inhibitor, ICG-001, was used for the inhibition of the Wnt/beta-catenin signaling in PTC cells. Results Vemurafenib-resistant PTC cells showed higher TRIB2 expression, upregulated ERK and AKT activation, enhanced invasive capacity, and increased epithelial-mesenchymal transition compared to the drug-sensitive groups. TRIB2 knockdown repressed the activation of ERK and AKT, inhibited invasion and EMT, and induced apoptosis of PTC cells. TRIB2 deficiency also enhanced the sensitivity of both PTC cells to vemurafenib. Vemurafenib-resistant PTC cells showed elevated expression of beta-catenin in both cytoplasm and nucleus. The pre-incubation of cells with beta-catenin inhibitor significantly inhibited TRIB2 expression, suppressed EMT, and repressed the activation of ERK and AKT in vemurafenib-resistant cells. Conclusion Our study showed that the upregulation of TRIB2 by the Wnt/beta-catenin activation confers resistance to vemurafenib in PTC with BRAF(V600) mutation. These findings support the potential use of TRIB2 as a therapeutic target for resistant PTC.