Kinase mutations in cancer: chinks in the enemy's armour?

Over the past few years, a revolution has transformed the oncology field. This revolution is characterized by two main features. The first is the introduction of the concept of individualized cancer therapy. The second is the development of drugs targeting molecules selectively altered in tumours. This review analyses these aspects by looking at the role that altered kinases and their inhibitors have played in this historical process.

Tumour progression is the result of the sequential accumulation of mutations in genes monitoring the rates of cell birth and cell death. The molecular profiling of cancers has shown that protein and lipid kinases are frequently altered in tumour cells. In most cases, these alterations translate in constitutively active proteins, which are amenable of therapeutic targeting. Intriguingly, even 'established' cancer cells remain somewhat 'addicted' to the deregulated activity of mutated kinases. This feature appears to be the basis for the ability of kinase inhibitors in controlling the development of a number of cancers. The therapeutic efficacy of kinase inhibitors is impaired by the emergence of tumour cells carrying 'resistance' mutations.

Many oncogenes are mutated kinase genes. In most cases, the mutations result in the constitutive activation of the affected kinase that can be pharmacologically inhibited. Unfortunately, upon treatment with kinase inhibitors, resistant clones develop rapidly, impairing their therapeutic effect. Strategies to overcome resistance are discussed as well as the possibility to target kinases regulating cancer stem cells.