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


Balabanov, S; Braig, M; Brümmendorf, T H (2014). Current aspects in resistance against tyrosine kinase inhibitors in chronic myelogenous leukemia. Drug Discovery Today: Technologies, 11:89-99.

Abstract

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 cover- ing 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.

Abstract

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 cover- ing 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:March 2014
Deposited On:09 Feb 2015 14:09
Last Modified:05 Apr 2016 18:48
Publisher:Elsevier
ISSN:1740-6749
Publisher DOI:https://doi.org/10.1016/j.ddtec.2014.03.003
PubMed ID:24847658

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