Assessing adaptation of the cancer kinome in response to targeted therapies.

Cancer cells are dependent on protein kinase signalling networks to drive proliferation and to promote survival, and, accordingly, kinases continue to represent a major target class for development of anti-cancer therapeutics. Kinase inhibitors nevertheless have yielded only limited success with many different malignancies due to the inability of single agents to sustain a durable clinical response. Cancer cell kinomes are highly resilient and able to bypass targeted kinase inhibition, leading to tumour resistance. A novel platform has been developed to analyse the activity of the expressed kinome using MIBs (multiplexed inhibitor beads), which consist of Sepharose beads with covalently immobilized inhibitors that preferentially bind activated kinases. Coupling MIB capture with MS (MIB-MS) allows simultaneous determination of the activity of over 75% of the expressed kinome, facilitating high-throughput assessment of adaptive kinase responses resulting from deregulated feedback and feedforward regulatory mechanisms. The adaptive response frequently involves transcriptional up-regulation of specific kinases that allow bypass of the targeted kinase. Understanding how the kinome reprogrammes to targeted kinase inhibition will allow novel therapeutic strategies to be developed for durable clinical responses.