Current aspects in resistance against tyrosine kinase inhibitors in chronic myelogenous leukemia

Resistance against tyrosine kinase inhibitors (TKIs) represents a relevant clinical problem in treatment of chronic myelogenous leukemia (CML). On the basis of their activity against the spectrum of BCR-ABL mutations that have shown to be the most prominent mechanism of resistance to imatinib, new TKIs have been classified as second generation (such as nilotinib, dasatinib and bosutinib) or third generation (also covering T315I such as ponatinib) TKIs. However, mutations in BCR-ABL only account for about half of the cases of treatment failure under TKI and other mechanisms either rendering the leukemic cells still dependent of BCR-ABL activity or supporting oncogenic properties of the leukemic cells independent of BCR-ABL signaling have been identified. A detailed understanding of the different underlying resistance mechanisms will be the prerequisite to eventually overcome clinical resistance and for the successful use of tailored combinations of targeted inhibitors in the future.