Battle at the Gates: Combating Mutant Kinases

This white paper describes how molecular therapeutics, that target protein kinases, represents a major advance in the treatment of disease, particularly cancer. These drugs have proven successful in treating some cancer patients, particularly those with pathologies derived by oncogenic forms of tyrosine kinases. However, the initial success of many of the first drugs developed, such as Gleevec® (imatinib), Iressa® (gefitinib) and Tarceva® (erlotinib), was tempered by patients who had responded initially to the drug but subsequently developed clinical resistance due mutant forms of Abl, Kit and EGFR receptors. However, not all protein kinase inhibitors developed are influenced by the amino acid at the gatekeeper position. This important realization implies testing various chemotypes for sensitivity to different gatekeeper sequences may be prudent to minimize the occurrence of this type of selective clinical resistance.