This article is more than 5 years old. Information may no longer be current.
Pathway key to BRAF V600E-mediated papillary thyroid cancer progression
Click Here to Manage Email Alerts
CHICAGO — The Wnt/beta-catenin signaling pathway may play an important role in the progression of BRAF V600E-mediated papillary thyroid cancer, according to study results presented at the Annual Meeting of the American Thyroid Association.
“Targeting the beta-catenin pathway may lead to increased therapeutic effects of the BRAF V600E inhibitor vemurafenib (Zelboraf, Genentech),” Yufei Shi, MD, researcher in the department of genetics at King Faisal Specialist Hospital and Research Center in Saudi Arabia, told HemOnc Today. “Given increased iodine uptake by targeting beta-catenin, it may also benefit radioactive iodine treatment, especially in patients with advanced or metastatic thyroid cancer resistant to iodine.”
BRAF V600E mutations are the most common genetic alternations in papillary thyroid cancer. They are the key driver of papillary thyroid cancer tumorigenesis via constitutive activation of the MAPK signaling pathway, according to study background.
Beta-catenin — encoded by the CTNNB1 gene — often is overexpressed in papillary thyroid cancer and mutated in anaplastic thyroid cancer.
Prior research suggested BRAF V600E-driven tumors rely on Wnt/beta-catenin signaling to sustain progression and growth; however, investigators do not understand all aspects of this interaction.
Shi and colleagues used a genetically engineered mouse model to assess the role of beta-catenin in BRAF V600Edriven thyroid cancer. The model included two genetically engineered strains — LSL-BRAF V600E and LSL-CTNNB1 null. Investigators bred these mice with TPO-Cre mice to produce thyroid-specific expression of BRAF V600E CTNNB1 null and BRAF V600E CTNNB1 wild-type strains.
Researchers evaluated thyroid tumor progression and survival in the CTNBB1 null and CTNNB1 wild-type models, and they observed overexpression of CTNNB1 in thyroid tumors in the CTNNB1 wild-type models.
“Following CTNNB1 knockout, thyroid tumors became more localized with evidence of redifferentiation into follicular architecture,” Shi and colleagues wrote.
OS increased by more than 50% in the CTNNB1 null model during the 13-month observation period (P < .001).
Attenuation of Wnt/beta-catenin signaling was linked to a significant reduction in tumor growth and prolonged OS. This appeared associated with multiple mechanisms, including downregulation of MAPK, PI3K/Akt, transforming growth factor beta signaling pathways, loss of epithelial-mesenchymal transition, upregulation of E-cadherin and genes in thyroid hormone synthesis, and improved immune surveillance by natural killer cell activation, Shi said.
In addition, PET/CT scans showed significantly greater thyroid uptake of I-124 in the CTNNB1 null mice than in CTNNB1 wild-type mice.
“We plan to conduct a study in vivo using the beta-catenin inhibitor against BRAF V600E-mediated thyroid cancer in our mouse model to evaluate the effect on thyroid uptake and tumor growth,” Shi told HemOnc Today. – by Jennifer Southall
Reference:
Zou M, et al. Highlighted Oral Abstract 1. Presented at: Annual Meeting of the American Thyroid Association; Oct. 30-Nov. 3, 2019; Chicago.
Disclosures: The authors report no relevant financial disclosures.