Targeted Therapy with Imatinib: An Exception or a Rule?

The discovery of STI571, a drug targeting the tyrosine kinase activity of Bcr-Abl, c-Kit, and platelet-derived growth factor receptor (PDGFR), has demonstrated the feasibility of ATP-competitive small-molecule kinase inhibitors for the chronic treatment of molecularly defined cancers. The presence of an activated form of protein kinases targeted by STI571 in various malignancies appears to be mandatory for a clinical response to this drug. This also indicates that a certain subset of molecularly defined tumors depends upon the overactivation of one or more signaling pathways, which can be attacked by targeted therapy. The finding that STI571 resistance is often associated with mutations in the kinase domain unambiguously demonstrates that the targets of STI571 in these tumors are Bcr-Abl, c-Kit, and/or PDGFR. Generation of resistance to STI571 is most likely due to the binding mode of STI571 that stabilizes the inactive conformation of the target kinases. Recent mutational analysis combined with structural biology has provided the basis for the understanding of the binding mode of STI571, and the resistance mechanisms as well as activation mechanisms of Bcr-Abl, c-Kit, and PDGFR. Although this binding mode is key for the exquisite selectivity and tolerability of STI571, it is also its “weakness”, because it allows mutations to occur in the target kinase which appear not to affect the normal function of the kinase. Therefore, for an effective long-term cancer therapy with ATP-competitive small-molecule kinase inhibitors, it appears necessary to use more than one kinase inhibitor targeting different conformations of the same kinase, or each inhibitor needs to be aimed at a specific mutant and downstream signaling element.