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

Abstract

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 BRAF 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 BRAF 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, BRAF-bearing TC cells were treated with BRAF 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 ( < 0.05), increased G2-phase cell cycle arrest and induced apoptosis ( < 0.05). In our TC xenograft model, the combination of Vemurafenib and Bortezomib significantly reduced tumor size ( < 0.05) and expression of the markers of cell growth and proliferation, Ki-67 and cyclin D1 ( < 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.

Expression of CXCR4 and CXCR7 in papillary thyroid carcinoma and adjacent tissues and their relationship with pathologic indicators of tumor aggressiveness

“…A novel preclinical study of mebendazolen demonstrated that it had promising therapeutic implications for patients with treatment refractory papillary thyroid cancer [12]. Treatment with the combination of the BRAF inhibitor Vemurafenib and Bortezomib accelerate mitochondrial dysregulation and apoptosis of TC cells Endocrine Journal Advance Publication [13]. But these drugs are not widely applied to in clinical practice.…”

Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals

“…On the other hand, Zecchin and colleagues clearly demonstrated that proteasome inhibitors possess a significant selectivity toward BRAF V600E -mutant colorectal cancer cells as a consequence of persistent BRAF signaling and a nononcogenic addiction to the proteasome function in those cells [57]. Furthermore, the combination of bortezomib and vemurafenib was shown to produce synergistic antitumor effects in thyroid cancer, both in vitro and in a xenograft model [58]. In the present study, we show that our vemurafenib-resistant cells were more sensitive to bortezomib than parental cells.…”

Combinatorial Therapies in Thyroid Cancer: An Overview of Preclinical and Clinical Progresses

“…Most importantly, the doses of the two drugs were reduced in the animal model, while the synergistic antitumour effects were preserved. In vitro assays studying the invasion suggested that the treatment could also play a role in the metastatic process [57]. The redifferentiation of cells harboring the BRAF V600E mutation was reported to be associated with an increase of radioiodine uptake and was evaluated with the combination of BRAF/MEK inhibitors (dabrafenib/selumetinib) and HER1/2 inhibitor (lapatinib).…”