Bortezomib sensitizes thyroid cancer to BRAF inhibitor in vitro and in vivo.

Although overall survival rate for patients with thyroid cancer (TC) is high, there is an alarming 10-year recurrence rate of up to 30% conferring a ~50% survival among these high-risk patients. The BRAFV600E mutation is estimated to be present in over 50% of papillary thyroid cancer (PTC) cases besides being associated with carcinogenesis and poor prognosis. We assessed the status of NF-κB, Ki-67, cyclin D1 and BRAFV600E in TC tissues and TC cell lines using immunohistochemistry and Western blot analysis. Concurrently, we evaluated the outcomes of combined targeting of the proteasome pathway in addition to selective BRAF inhibitors in cases of PTC. In this study, BRAFV600E-bearing TC cells were treated with BRAFV600E inhibitor, Vemurafenib alone or in combination with the proteasome inhibitor, Bortezomib. The combination of both drugs showed synergistic effects as evidenced by cell growth inhibition (P < 0.05), increased G2-phase cell cycle arrest and induced apoptosis (P < 0.05). In our TC xenograft model, the combination of Vemurafenib and Bortezomib significantly reduced tumor size (P < 0.05) and expression of the markers of cell growth and proliferation, Ki-67 and cyclin D1 (P < 0.001), when compared to monotherapy. Further analysis demonstrated that treatment with Bortezomib sensitized TC cells to Vemurafenib via mitochondrial dysregulation and apoptosis of TC cells, as evidenced by the increase in the expression of p53, Noxa protein, the loss of mitochondrial membrane potential, cytochrome c release and Poly (ADP-ribose) polymerase cleavage. Our results demonstrate a strong clinical potential for the combination of the Bortezomib and the BRAF inhibitor Vemurafenib as an efficient therapeutic approach for the treatment of TC.

Tsumagari K ，Abd Elmageed ZY ，Sholl AB ，Green EA ，Sobti S ，Khan AR ，Kandil A ，Murad F ，Friedlander P ，Boulares AH ，Kandil E ... -  《-》

The MEK1/2 Inhibitor AZD6244 Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib.

Song H ，Zhang J ，Ning L ，Zhang H ，Chen D ，Jiao X ，Zhang K ... -  《MEDICAL SCIENCE MONITOR》

Combination Treatment with the BRAF(V600E) Inhibitor Vemurafenib and the BH3 Mimetic Navitoclax for BRAF-Mutant Thyroid Carcinoma.

Jeong JH ，Oh JM ，Jeong SY ，Lee SW ，Lee J ，Ahn BC ... -  《-》

Signal transducer and activator of transcription 3 inhibition alleviates resistance to BRAF inhibition in anaplastic thyroid cancer.

Wang Y ，Hu Z ，Ma W ，Niu Y ，Su J ，Zhang L ，Zhao P ... -  《-》

Fine-Tuning Lipid Metabolism by Targeting Mitochondria-Associated Acetyl-CoA-Carboxylase 2 in BRAF(V600E) Papillary Thyroid Carcinoma.

Valvo V ，Iesato A ，Kavanagh TR ，Priolo C ，Zsengeller Z ，Pontecorvi A ，Stillman IE ，Burke SD ，Liu X ，Nucera C ... -  《-》