Monotherapy vs combination therapy evaluation of FDA-approved TKIs targeting PDGFR for the treatment of thyroid cancer

Thyroid cancer is the 5th most common type of cancer in the USA. There are various tyrosine kinase inhibitors (TKIs) approved by the US FDA for its treatment but all the approved drugs target receptor tyrosine kinase through different pathways. On 4th May, 2018, a combination of Dabrafenib and Trametinib/Dab-Tra has been approved by US FDA for the treatment of anaplastic thyroid cancer (ATC) that highlights the importance of combination therapy in its treatment. As this combination has some major safety concerns, it creates a need to find an alternative combination. In this manuscript, we have tested the potential of all the combinations possibly made by combining different FDA-approved TKIs against Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) using simultaneous docking. We found that the best combination amongst all is of Pralsetinib and Trametinib/Pra-Tra with a docking score of −14.47 kcal/mol. MD simulation was also carried out and the RMSF and the RMSD of the protein in the bound form suggested that its Model 1 is best amongst all. These results were further strengthened using FEL. The PCA was performed that suggested the structural conformations observed beyond 60 ns are closer to a stable state. The outcome reveals that there are various combinations of TKIs that have the potential to be more efficacious for the treatment of thyroid cancer than Dab-Tra. We also found that a combinatorial approach with TKIs could prove to be better than monotherapy. Further <i>in-vitro</i> and <i>in-vivo</i> studies are required to strengthen the results obtained through <i>in-silico</i> experiment.