Better understanding the harmony between targets

One biological reason for PKI failure in clinical trials is that disease is often not orchestrated by just one kinase target or pathway. For example, when only a single kinase is targeted in cancer therapy, the tumor can escape inhibition due to intrinsic resistance, target mutations or acquired activation of alternative pathways. Overcoming these problems could require, for example, a rational design of a mutation-specific inhibitor or an inhibitor cocktail that combines a PKI candidate with one or more (non-)approved drugs, including non-PKIs.

Combination therapies increase PKI therapeutic responses by interfering in the disease’s pivotal pathways and decreasing the likelihood of acquired resistance. Therefore, to develop a successful PKI combination treatment, it is essential to know the resistance mechanism firstly and secondly to have a deep understanding of the MOA of both individual drugs and drug combinations specific to the disease model used.