Treatment options for advanced metastatic thyroid cancer patients are limited. 
Vemurafenib, a BRAFV600E inhibitor, has shown promise in clinical trials 
although cellular resistance occurs. Combination therapy that includes BRAFV600E 
inhibition and avoids resistance is a clinical need. We used an in vitro model 
to examine combination treatment with vemurafenib and mammalian target of 
rapamycin (mTOR) inhibitors, metformin and rapamycin. Cellular viability and 
apoptosis were analyzed in thyroid cell lines by trypan blue exclusion and TUNEL 
assays. Combination of vemurafenib and metformin decreased cell viability and 
increased apoptosis in both BCPAP papillary thyroid cancer cells and 8505c 
anaplastic thyroid cancer cells. This combination was also found to be active in 
vemurafenib-resistant BCPAP cells. Changes in expression of signaling molecules 
such as decreased mTOR expression in BCPAP and enhanced inhibition of 
phospho-MAPK in resistant BCPAP and 8505c were observed. The second combination 
of vemurafenib and rapamycin amplified cell death in BCPAP cells. We conclude 
that combination of BRAFV600E and mTOR inhibition forms the basis of a treatment 
regimen that should be further investigated in in vivo model systems. Metformin 
or rapamycin adjuvant treatment may provide clinical benefits with minimal side 
effects to BRAFV600E-positive advanced thyroid cancer patients treated with 
vemurafenib.