plx-4720 and Carcinoma--Papillary

The BRAF(V600E) mutation is found in approximately 40% of papillary thyroid cancers (PTC). Mice with thyroid-specific expression of Braf(V600E) (TPO-Braf(V600E)) develop PTC rapidly with high levels of serum thyroid-stimulating hormone (TSH). It is unclear to what extent the elevated TSH contributes to tumor progression. To investigate the progression of Braf(V600E)-induced PTC (BVE-PTC) under normal TSH, we transplanted BVE-PTC tumors subcutaneously into nude and TPO-Braf(WT) mice. Regression of the transplanted tumors was observed in both nude and TPO-Braf(WT) mice. They were surrounded by heavy lymphocyte infiltration and oncogene-induced senescence (OIS) was demonstrated by strong β-gal staining and absence of Ki-67 expression. In contrast, BVE-PTC transplants continued to grow when transplanted into TPO-Braf(V600E) mice. The expression of Trp53 was increased in tumor transplants undergoing OIS. Trp53 inactivation reversed OIS and enabled tumor transplants to grow in nude mice with characteristic cell morphology of anaplastic thyroid cancer (ATC). PTC-to-ATC transformation was also observed in primary BVE-PTC tumors. ATC cells derived from Trp53 knockout tumors had increased PI3K/AKT signaling and became resistant to Braf(V600E) inhibitor PLX4720, which could be overcome by combined treatment of PI3K inhibitor LY294002 and PLX4720. In conclusion, BVE-PTC progression could be contained via p53-dependent OIS and TSH is a major disruptor of this balance. Simultaneous targeting of both MAPK and PI3K/AKT pathways offer a better therapeutic outcome against ATC. The current study reinforces the importance of rigorous control of serum TSH in PTC patients.

Topics: Animals; Carcinoma; Carcinoma, Papillary; Cellular Senescence; Chromones; Disease Progression; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Genes, p53; Humans; Indoles; Lymphocytes, Tumor-Infiltrating; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Nude; Mice, Transgenic; Morpholines; Mutation, Missense; Neoplasm Proteins; Neoplasm Transplantation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Signal Transduction; Sulfonamides; Thyroid Neoplasms; Thyrotropin; Tumor Suppressor Protein p53

BRAF is a main oncogene in human thyroid cancer. Here, we show that BRAF depletion by siRNA or inhibition of its activity by treatment with BRAF inhibitor PLX4720 decreases migration and invasion in thyroid cancer cells expressing oncogenic (V600E)BRAF through a MEK/ERK-dependent mechanism, since treatment with the MEK inhibitor U0126 exerts the same effect. Moreover, over-expression of (V600E)BRAF increases migration and invasion of wild-type BRAF thyroid cells. Using the same strategies, we demonstrate that these effects are mediated by upregulation of the transcriptional repressor Snail with a concomitant decrease of its target E-cadherin, both hallmarks of EMT. These results reveal a novel (V600E)BRAF-induced mechanism in thyroid tumours progression and provides a rationale for using the PLX4720 inhibitor to target (V600E)BRAF signalling to effectively control progression of thyroid cancer.

Topics: Antigens, CD; Butadienes; Cadherins; Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Cell Movement; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Indoles; MAP Kinase Kinase Kinases; Mutation, Missense; Neoplasm Invasiveness; Nitriles; Proto-Oncogene Proteins B-raf; RNA, Small Interfering; Snail Family Transcription Factors; Sulfonamides; Thyroid Cancer, Papillary; Thyroid Neoplasms; Transcription Factors