Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABLand BCR-ABL-T315I Mian, Afsar Ali Metodieva, Anna Badura, Susanne Khateb, Mamduh Najajreh, Yousef Ottmann, Oliver Gerhard Mahajna, Jamal Ruthardt, Martin 2018-09-05T08:29:16Z 2018-09-05T08:29:16Z 2012-09-17
dc.description.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. en_US
dc.description.sponsorship This study was supported by a grant from the German Research Foundation (DFG) to MR, JM and YN (DFG-RU 728/3-2). en_US
dc.identifier.issn 1471-2407
dc.language.iso en_US en_US
dc.publisher BioMed Central en_US
dc.subject Philadelphia chromosome en_US
dc.subject BCR/ABL en_US
dc.subject gatekeeper” mutation T315I en_US
dc.subject Allosteric inhibition en_US
dc.subject Abl kinase inhibitors en_US
dc.subject Molecular therapy en_US
dc.title Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABLand BCR-ABL-T315I en_US
dc.type Article en_US
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