CML has become the paradigm for targeted cancer treatment. The introduction of imatinib has led to a dramatic improvement of prognosis in chronic phase patients when compared to conventional chemotherapy. The use of small molecule kinase inhibitors has been extended to other entities, and thereby redefined the management of cancer, in general. By virtue of their specific mode of action and the addiction of CML to BCR-ABL, resistance to therapeutic kinase inhibitors is based on a limited number of mechanisms that were elucidated by focusing on changes taking place at the target kinase itself. This scenario is completely different from conventional chemotherapy, where resistance is of multifactorial origin, and detection of resistance mechanisms generally does not have an immediate impact on further treatment. In contrast, understanding resistance in kinase inhibitor based therapies clearly affects subsequent treatment, since specific point mutations may prevent binding of a certain class of compounds, while a structurally different substances still can bind and do its job. When amplification of the BCR-ABL gene occurs, higher doses of a kinase inhibitor may overcome residual BCR-ABL activity. Therefore, detection of specific mechanisms of resistance in an individual patient certainly has an immediate impact on further treatment, and the determination of individual resistance profiles for different classes of BCR-ABL kinase inhibitors allows the design of sequential or combinatorial treatment strategies, thereby limiting the number of possible "escape" mutations. Once resistance to imatinib has occurred, sequencing of the BCR-ABL kinase may demonstrate a resistance mutation, and switching to an appropriate alternate compound may overcome a mutated disease clone.
The finding of target kinase domain mutations giving rise to resistance toward kinase inhibitors has been reproduced in other examples of targeted cancer treatments. Examples are NSCL, where exchanges in the EGFR kinase domain can abrogate binding and inhibition of EGFR kinase inhibitors such as gefitinib, and mutations in KIT or FIP1L1-PDGFRalpha in imatinib resistant gastrointestinal stromal tumor (GIST), or chronic eosinophilic leukemia, respectively. Understanding molecular changes underlying resistance to therapeutically used kinase inhibitors will undoubtedly improve treatment strategies. Applying this knowledge to the individual patient requires cytogenetic and molecular monitoring, including mutational analysis.
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