Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib.
OBJECTIVE
Chronic myeloid leukemia (CML) is effectively treated with imatinib. However, reactivation of Bcr-Abl via kinase domain mutations that reduce sensitivity to imatinib can cause relapse. As combination therapy is frequently used to prevent emergence of resistance, the combination of imatinib with an inhibitor of imatinib-resistant Bcr-Abl mutants (e.g., Src/Abl inhibitors AP23848 and BMS-354825) was investigated.


METHODS
To test this approach, cellular proliferation and Bcr-Abl tyrosine phosphorylation assays were done on Ba/F3 cells expressing wild-type (WT) Bcr-Abl and four common imatinib-resistant mutants (Y253F, E255K, T315I, and M351T). Colony-forming assays with primary CML cells were also done.


RESULTS
Both Src/Abl inhibitors retained full inhibitory capacity when coadministered with imatinib at concentrations above typical clinical levels. For cells expressing WT Bcr-Abl or the marginally imatinib-resistant mutant M351T, inclusion of imatinib at therapeutic levels enhanced the effects of the Src/Abl inhibitors. By comparison, for the highly imatinib-resistant mutants Y253F and E255K, inclusion of imatinib at clinical levels resulted in only a slight enhancement beyond the effects of the Src/Abl inhibitors. None of the inhibitors affected Bcr-Abl T315I cells. Colony-forming assays with primary CML cells yielded analogous results.


CONCLUSIONS
Our results indicate that Src/Abl inhibitors are compatible with imatinib and suggest that combined Abl inhibitor therapy is a feasible treatment strategy for patients with CML.
O'Hare
Thomas
T
Howard Hughes Medical Institute, Oregon Health and Science University, Portland 97239, USA. oharet@ohsu.edu
Walters
Denise K
DK
Stoffregen
Eric P
EP
Sherbenou
Daniel W
DW
Heinrich
Michael C
MC
Deininger
Michael W N
MW
Druker
Brian J
BJ
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D049109:Cell Proliferation; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D009154:Mutation; D019000:Phosphotyrosine / Q000737:chemistry; D010879:Piperazines / Q000494:pharmacology*; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D013234:Stem Cells / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism*
C502390:AP23848; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D019000:Phosphotyrosine; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; D000069439:Dasatinib