Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABLand BCR-ABL-T315I
| dc.contributor.author | Mian, Afsar Ali | |
| dc.contributor.author | Metodieva, Anna | |
| dc.contributor.author | Badura, Susanne | |
| dc.contributor.author | Khateb, Mamduh | |
| dc.contributor.author | Najajreh, Yousef | |
| dc.contributor.author | Ottmann, Oliver Gerhard | |
| dc.contributor.author | Mahajna, Jamal | |
| dc.contributor.author | Ruthardt, Martin | |
| dc.date.accessioned | 2018-09-05T08:29:16Z | |
| dc.date.available | 2018-09-05T08:29:16Z | |
| dc.date.issued | 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.identifier.uri | https://dspace.alquds.edu/handle/20.500.12213/839 | |
| 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 |