Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated.
CD70 expression was associated with the presence of a precursor papillary thyroid carcinoma and the presence of BRAF V600E mutations in the anaplastic thyroid cancer lesion.
BRAF V600E mutation was the most common mutation, which is present in almost all HVPTC samples (16/17, 94%), most CPTC samples (20/26, 77%), and none of the ATC and PDTC samples.
The combinatorial treatment of PLX4032 and PHA665752, a c-Met inhibitor reversed EMT.Similar results were confirmed in vivo. c-Met-mediated reactivation of the PI3K/AKT pathway contributes to the drug resistance to PLX4032 in BRAF (V600E) mutant anaplastic thyroid cancer cells and further promotes tumor cell migration and invasion by upregulated EMT mechanism.
Similar results were confirmed by in vivo study with orthotopic xenograft mouse model. c-Met-mediated reactivation of the PI3K/AKT pathway and MAPK pathway contributes to the relative insensitivity of BRAF (V600E) mutant anaplastic thyroid cancer cells to PLX4032.
Our results suggest that angiogenic/cachectic and pro-inflammatory/immune response factors could play a crucial role in BRAF(V600E)-positive human ATC aggressiveness.
We report a 65-year-old woman with anaplastic thyroid carcinoma (BRAF V600E mutation) who had lymph node metastases (pT4 N1b) treated by total thyroidectomy, postoperative radiotherapy, adjuvant chemotherapy (paclitaxel and pazopanib) and targeted therapy (vemurafenib).
Further, type I collagen enhanced the motility of Braf(V600E)/Pten(-/-)/TPO-Cre tumor cells in vitro In clinical specimens, we found COL1A1 and LOX to be upregulated in PTC and expressed at highest levels in PDTC and anaplastic thyroid cancer.
The (V600E) BRAF mutation was observed in three ATCs; the results about the inhibition of proliferation by CLM29 and CLM24, obtained in ATC from tumors with (V600E) BRAF mutation were similar to those from tumors without BRAF mutation.
BRAF V600E and RAS mutations were mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53.
In papillary thyroid cancer (PTC) and papillary-derived anaplastic thyroid cancer (ATC), the BRAF(V600E) mutation promotes follicular cell transformation.
This is the largest study on the aggressive role of TERT promoter mutations in ATC, demonstrating an association of TERT C228T with BRAF V600E, older patient age, and tumor distant metastasis in ATC.
Combined BRAF(V600E)- and SRC-inhibition induces apoptosis, evokes an immune response and reduces tumor growth in an immunocompetent orthotopic mouse model of anaplastic thyroid cancer.
We characterized and utilized mouse cell lines derived from PTC and ATC tumors arising in genetically engineered mice with thyroid-specific expression of endogenous Braf(V600E/WT) and deletion of either Trp53 (p53) or Pten.
Here, we use mice carrying a conditional allele of PIK3CA to demonstrate that, although mutationally activated PIK3CA(H1047R) is unable to drive transformation on its own, when combined with BRAF(V600E) in thyrocytes, this leads to development of lethal ATC in mice.
First, absent/faint staining for BRAF V600E correlates perfectly with the lack of the BRAF(T1799A) mutation, whereas strong staining is highly specific for the BRAF(T1799A) mutation in PTCs, PDTCs, and ATCs.