Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I
- 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.
Author: | Afsar Ali MianORCiDGND, Anna Metodieva, Susanne BaduraGND, Mamduh Khateb, Nili Ruimi, Yousef Najajreh, Oliver G. OttmannORCiDGND, Jamal Mahajna, Martin RuthardtORCiD |
---|---|
URN: | urn:nbn:de:hebis:30:3-264119 |
DOI: | https://doi.org/10.1186/1471-2407-12-411 |
ISSN: | 1471-2407 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/22985168 |
Parent Title (English): | BMC cancer |
Publisher: | BioMed Central |
Place of publication: | London |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2012/09/17 |
Date of first Publication: | 2012/09/17 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2012/11/05 |
Tag: | Abl kinase inhibitors; Allosteric inhibition; BCR/ABL; Molecular therapy; Philadelphia chromosome; “gatekeeper” mutation T315I |
Volume: | 12 |
Issue: | 411 |
Page Number: | 8 |
Note: | © 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. |
HeBIS-PPN: | 358184304 |
Institutes: | Medizin / Medizin |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - Namensnennung 2.0 |