Simultaneous suppression of the MAP kinase and NF-κB pathways provides a robust therapeutic potential for thyroid cancer

• We examined simultaneous targeting of two pathways, the MAP kinase and NF-κB pathways.
• We used two FDA approved drugs, AZD6244 and Bortezomib.
• Dual drug treatment caused significant apoptosis in vitro.
• Dual drug treatment caused the inhibition of cell growth and migration in vitro.
• Dual drug treatment in the xenograft model caused a significant reduction in tumor size.

The MAP kinase and NF-κB signaling pathways play an important role in thyroid cancer tumorigenesis. We aimed to examine the therapeutic potential of dually targeting the two pathways using AZD6244 and Bortezomib in combination. We evaluated their effects on cell proliferation, cell-cycle progression, apoptosis, cell migration assay, and the activation of the MAPK pathway in vitro and the in vivo using tumor size and immunohistochemical changes of Ki67 and ppRB. We found inhibition of cell growth rate by 10%, 20%, and 56% (p < 0.05), migration to 55%, 61%, and 29% (p < 0.05), and induction of apoptosis to 10%, 15%, and 38% (p < 0.05) with AZD6244, Bortezomib, or combination, respectively. Induction of cell cycle arrest occurred only with drug combination. Dual drug treatment in the xenograft model caused a 94% reduction in tumor size (p < 0.05) versus 15% with AZD6244 and 34% with Bortezomib (p < 0.05) and also reduced proliferative marker Ki67, and increased pRb dephosphorylation. Our results demonstrate a robust therapeutic potential of combining AZD6244 and Bortezomib as an effective strategy to overcome drug resistance encountered in monotherapy in the treatment of thyroid cancer, strongly supporting clinical trials to further test this strategy.