The dynamic nature of the kinome

Abstract

Recent advances in proteomics have facilitated the analysis of the kinome 'en masse'. What these studies have revealed is a surprisingly dynamic network of kinase responses to highly selective kinase inhibitors, thereby illustrating the complex biological responses to these small molecules. Moreover these studies have identified key transcription factors, such as c-Myc and FOXO (forkhead box O), that play pivotal roles in kinome reprogramming in cancer cells. Since many kinase inhibitors fail despite a high efficacy of blocking their intended targets, elucidating kinome changes at a more global level will be essential to understanding the mechanisms of kinase inhibitor pharmacology. The development of technologies to study the kinome, as well as examples of kinome resilience and reprogramming, will be discussed in the present review.

Figure 1. Monitoring kinome reprogramming in cells and tumours using MIBs in combination with MS

Endogenous kinases are affinity-purified from cell lysates using MIB/MS and both MIB-binding ratios and phosphorylation of kinase activation loops were determined using qMS. Of the kinases identified in a recent study [21], only 4% are current targets for kinase inhibitor drugs, the remainder representing the untargeted cancer kinome [51].

Figure 2. Model describing the effects of targeted inhibition of MEK1/2 by AZD6244 in TNBC

Shown is the proposed kinome reprogramming caused by loss of c-Myc protein and subsequent derepression of transcription of growth-promoting RTKs to reactivate MAPK signalling as described in Duncan et al. [21].