Results of researches from C S Monast and M J Lazzara highlight numerous other considerations that determine biochemical efficacy beyond those reflected by equilibrium affinities. By integrating these considerations, their model also predicts minimum therapeutic combination concentrations to maximally reduce receptor phosphorylation.

Their finding that the abilities of cetuximab and gefitinib to antagonize EGFR phosphorylation are determined by processes beyond those describing equilibrium drug binding motivates new consideration of optimal design strategies for EGFR-targeted therapeutics. To the extent that EGFR phosphorylation level correlates with clinical efficacy, these results also identify possible factors that could underlie the differential effectiveness of the therapeutics among patients.

The identification of EGFR dephosphorylation kinetics as a key determinant of therapeutic biochemical efficacy is intriguing given that the activities of protein tyrosine phosphatases that regulate EGFR are altered in certain cancer settings.

Their results also predict IC₅₀ dependence on the rates of drug and ligand association and dissociation, even for constant affinities. Their prediction that slowing EGFR gefitinib binding and dissociation cycling decreases IC₅₀ is consistent with the observation that slower erlotinib cycling promotes growth inhibition of lung and brain cancer cells.

Reference

 Identifying Determinants of EGFR-Targeted Therapeutic Biochemical Efficacy Using Computational Modeling, CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e141; doi:10.1038/psp.2014.39