Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I.

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.

• Authors: Afsar Ali Mian, Anna Metodieva, Susanne Badura, Mamduh Khateb, Nili Ruimi, Yousef Najajreh, Oliver Gerhard Ottmann, Jamal Mahajna, Martin Ruthardt
• Journal: BMC cancer (BMC Cancer) Vol. 12 Pg. 411 (Sep 17 2012) ISSN: 1471-2407 [Electronic] England
• PMID: 22985168 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• GNF-2 compound
• Protein Kinase Inhibitors
• Pyrimidines
• Thiazoles
• Fusion Proteins, bcr-abl
• Dasatinib

Topics

• Allosteric Regulation (drug effects)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic (drug effects, genetics)
• Cells, Cultured
• Colony-Forming Units Assay
• Dasatinib
• Female
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics)
• Gene Expression
• Hematopoietic Stem Cells (metabolism)
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (genetics)
• Mice
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Thiazoles (pharmacology)