TY - JOUR A1 - Mian, Afsar Ali A1 - Metodieva, Anna A1 - Badura, Susanne A1 - Khateb, Mamduh A1 - Ruimi, Nili A1 - Najajreh, Yousef A1 - Ottmann, Oliver G. A1 - Mahajna, Jamal A1 - Ruthardt, Martin T1 - Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I T2 - BMC cancer N2 - 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. KW - Philadelphia chromosome KW - BCR/ABL KW - “gatekeeper” mutation T315I KW - Allosteric inhibition KW - Abl kinase inhibitors KW - Molecular therapy Y1 - 2012 UR - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/26411 UR - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-264119 SN - 1471-2407 N1 - © 2012 Mian et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. VL - 12 IS - 411 PB - BioMed Central CY - London ER -