Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABLand BCR-ABL-T315I
Date
2012-09-17
Authors
Mian, Afsar Ali
Metodieva, Anna
Badura, Susanne
Khateb, Mamduh
Najajreh, Yousef
Ottmann, Oliver Gerhard
Mahajna, Jamal
Ruthardt, Martin
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
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.
Description
Keywords
Philadelphia chromosome , BCR/ABL , gatekeeper” mutation T315I , Allosteric inhibition , Abl kinase inhibitors , Molecular therapy