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

Area of Science:

• Oncology
• Pharmacology
• Computational Chemistry

Background:

• Thyroid cancer is a significant health concern in the USA.
• Current FDA-approved tyrosine kinase inhibitors (TKIs) target receptor tyrosine kinases via distinct pathways.
• The combination of Dabrafenib and Trametinib (Dab-Tra) is FDA-approved for anaplastic thyroid cancer but has safety concerns, necessitating alternative combinations.

Purpose of the Study:

• To investigate the efficacy of novel combinations of FDA-approved TKIs against Platelet-Derived Growth Factor Receptor Alpha (PDGFRA).
• To identify a potentially safer and more effective TKI combination therapy for thyroid cancer compared to existing treatments.

Main Methods:

• Simultaneous molecular docking was employed to evaluate all possible combinations of FDA-approved TKIs against PDGFRA.
• Molecular Dynamics (MD) simulations, Free Energy Landscape (FEL) analysis, and Principal Component Analysis (PCA) were performed to assess the stability and conformational dynamics of the best-performing complex.

Main Results:

• The combination of Pralsetinib and Trametinib (Pra-Tra) exhibited the highest docking score (-14.47 kcal/mol), indicating strong binding affinity.
• MD simulations and subsequent analyses (RMSF, RMSD, FEL, PCA) confirmed the stability of the Pra-Tra complex, with specific models and conformations identified as optimal.
• The study identified several TKI combinations with potential for greater efficacy than the current Dab-Tra therapy.

Conclusions:

• Combinatorial TKI therapy holds significant promise for improving thyroid cancer treatment outcomes compared to monotherapy.
• The Pra-Tra combination represents a promising candidate for further investigation in preclinical and clinical settings.
• Further in vitro and in vivo studies are warranted to validate these in silico findings and advance thyroid cancer therapeutics.