BRAF(V600E) mutation exerts an essential oncogenic function in many tumors, 
including papillary thyroid carcinoma (PTC). Although BRAF(V600E) inhibitors are 
available, lack of response has been frequently observed. To study the mechanism 
underlying intrinsic resistance to the mutant BRAF(V600E) selective inhibitor 
vemurafenib, we established short-term primary cell cultures of human 
metastatic/recurrent BRAF(V600E)-PTC, intrathyroidal BRAF(V600E)-PTC, and normal 
thyroid (NT). We also generated an early intervention model of human 
BRAF(V600E)-PTC orthotopic mouse. We find that metastatic BRAF(V600E)-PTC cells 
elicit paracrine-signaling which trigger migration of pericytes, blood 
endothelial cells and lymphatic endothelial cells as compared to BRAF(WT)-PTC 
cells, and show a higher rate of invasion. We further show that vemurafenib 
therapy significantly suppresses these aberrant functions in non-metastatic 
BRAF(V600E)-PTC cells but lesser in metastatic BRAF(V600E)-PTC cells as compared 
to vehicle treatment. These results concur with similar folds of down-regulation 
of tumor microenvironment-associated pro-metastatic molecules, with no effects 
in BRAF(WT)-PTC and NT cells. Our early intervention preclinical trial shows 
that vemurafenib delays tumor growth in the orthotopic BRAF(WT/V600E)-PTC mice. 
Importantly, we identify high copy number gain of MCL1 (chromosome 1q) and loss 
of CDKN2A (P16, chromosome 9p) in metastatic BRAF(V600E)-PTC cells which are 
associated with resistance to vemurafenib treatment. Critically, we demonstrate 
that combined vemurafenib therapy with BCL2/MCL1 inhibitor increases metastatic 
BRAF(V600E)-PTC cell death and ameliorates response to vemurafenib treatment as 
compared to single agent treatment. In conclusion, short-term PTC and NT 
cultures offer a predictive model for evaluating therapeutic response in 
patients with PTC. Our PTC pre-clinical model suggests that combined targeted 
therapy might be an important therapeutic strategy for metastatic and refractory 
BRAF(V600E)-positive PTC.