Multiple targeted tyrosine kinase inhibition in the clinic: all for one or one for all?

Recent insight into the role of receptor tyrosine kinase function in cancer cells culminated in the design of highly selective tyrosine kinase inhibitors. After proof of concept for the clinical efficacy and tolerability of selective tyrosine kinase inhibitors, it was conceived that most tumours will depend on more than one signalling pathway for their growth and survival. As a consequence, different strategies were pursued to inhibit multiple signalling pathways or multiple steps in the same pathway either by the development of multi-targeted agents or the combination of single targeted drugs. The use of a combination of different compounds will be less convenient to the patient, may result in dosing mistakes and drug-drug interaction should be anticipated. However, this approach will enable the titration of the dose of either agent to optimize target inhibition. The use of multi-targeted agents will circumvent several of the problems of combination therapy. Clinical activity resulting in FDA approval for both BAY 43-9006 and SU11248 has been noted. However, optimal inhibition of several targets might not be feasible at a dose with acceptable toxicity.