Conclusion and Perspectives

Although the clinical efficacy of STI571 has clearly demonstrated the utility and the potential of kinase inhibitors, the defined etiologies of diseases associated with expression of mutated PDGFR, c-Kit and Abl may make the success of this kinase inhibitor as single agent unique for a limited set of cancers. On the other hand, STI571 has taught us several lessons:

1. Protein kinase inhibitors with a "reasonable selectivity" are feasible and can be used for the chronic treatment of cancer patients with an acceptable tol-erability and efficacy profile where the pathophysiology of the kinase target in the tumor is molecularly defined.

2. In almost all clinical studies with STI571, the clinical responses to drug treatment correlate with the presence of an activated form of the target ki-nase in the tumor. These findings indicate that at least some (subsets) of tumors may ultimately depend on the over-activation of one pathway which can be attacked using targeted therapy. To maximize the chances of success in targeted therapy it will be mandatory to stratify patients according to the relevance of the molecular target in the particular malignancy.

3. Although relapses under STI571 treatment may be due to various reasons, the finding that it is often associated with mutations in the kinase domain of the target enzyme unambiguously demonstrates that the target for STI571, thus far, can only be Bcr-Abl, c-Kit, and/or PDGFR.

4. The exquisite selectivity of STI571, which is achieved by targeting and/or inducing the "inactive conformation of the target kinase," is presumably key for the excellent tolerability to the drug but is at the same time also its "Achilles heel." The binding mode of STI571 to the target kinase allows mutations in residues that are not involved in ATP binding and consequently not deleterious to the normal function of the targeted kinase. Mutations leading to resistance are either less likely to occur, or will generate a different set of mutations if the compound targets the active rather than the inactive conformation. To optimize treatment, it appears obvious to use more than one kinase inhibitor targeting the same kinase, but different conformations.

5. A key to the discovery of new anti-cancer therapeutics is the selection of epidemiologically relevant, drugable protein kinase targets coupled to efficient lead optimization for potency, selectivity, efficacy, and biopharmaceu-tical properties. Mutational analysis combined with structural biology has provided the understanding on the activation mechanisms of Bcr-Abl, Kit, and PDGFR as well as to its resistance to STI571.

Protein kinase inhibitors have and will continue to offer new therapies in the coming years and have started to add novel treatment modalities for cancer. Consequently, an effective long-term management of cancer is still likely to require cocktails of drugs, each aimed at a specific mutant and pathway.

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