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Open Access 01-12-2012 | Research article

Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I

Authors: Afsar Ali Mian, Anna Metodieva, Susanne Badura, Mamduh Khateb, Nili Ruimi, Yousef Najajreh, Oliver Gerhard Ottmann, Jamal Mahajna, Martin Ruthardt

Published in: BMC Cancer | Issue 1/2012

Abstract

Background

Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses BCR to ABL resulting in deregulated ABL-tyrosine kinase activity. The constitutively activated BCR/ABL-kinase “escapes” the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. The ABL-kinase inhibitors (AKIs) Imatinib, Nilotinib or Dasatinib, which target the ATP-binding site, are effective in Ph + leukemia. Another molecular therapy approach targeting BCR/ABL restores allosteric inhibition. Given the fact that all AKIs fail to inhibit BCR/ABL harboring the ‘gatekeeper’ mutation T315I, we investigated the effects of AKIs in combination with the allosteric inhibitor GNF2 in Ph + leukemia.

Methods

The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC) from Ph + ALL-patients.

Results

Here, we show that GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner.

Conclusions

Our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants using a combination of AKIs and allosteric inhibitors.

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The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/12/411/prepub

Title: Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I
Authors: Afsar Ali Mian
Anna Metodieva
Susanne Badura
Mamduh Khateb
Nili Ruimi
Yousef Najajreh
Oliver Gerhard Ottmann
Jamal Mahajna
Martin Ruthardt
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/1471-2407-12-411

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