mTOR pathway overactivation in BRAF mutated papillary thyroid carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The mammalian target of rapamycin (mTOR) pathway is implicated in various cancers.
• While RET/PTC and RAS mutations activate the phosphatidylinositol-3-kinase/AKT pathway, the role of BRAF V600E in mTOR pathway dysregulation in thyroid neoplasia remains unclear.

Purpose of the Study:

• To investigate the activation status of the mTOR pathway in malignant thyroid lesions.
• To determine the correlation between mTOR pathway activation and known genetic alterations, specifically the BRAF V600E mutation.
• To elucidate the mechanisms driving mTOR pathway activation in thyroid cancer.

Main Methods:

• Immunohistochemical analysis of mTOR pathway proteins in thyroid cancer tissues.
• Transfection assays and small interfering RNA (siRNA) knockdown to assess BRAF's role in mTOR activation.
• Evaluation of rapamycin's effect on thyroid cancer cell lines with MAPK pathway mutations.

Main Results:

• mTOR pathway proteins were upregulated in thyroid cancer, particularly in conventional papillary thyroid carcinoma (cPTC).
• Overactivation of mTOR signaling was pronounced in cPTC with the BRAF V600E mutation.
• BRAF expression positively correlated with mTOR activation, potentially mediated by pLKB1 Ser428, suggesting a mechanism for BRAF mutation-induced mTOR upregulation. Cell lines with MAPK pathway mutations showed increased sensitivity to rapamycin.

Conclusions:

• The AKT/mTOR pathway is significantly overactivated in human cPTC harboring the BRAF V600E mutation.
• The mTOR pathway represents a potential therapeutic target for enhancing treatment outcomes in specific thyroid carcinomas, notably those with the BRAF V600E mutation.