TY - JOUR
T1 - Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib
AU - Corbin, Amie S.
AU - La Rosée, Paul
AU - Stoffregen, Eric P.
AU - Druker, Brian J.
AU - Deininger, Michael W.
PY - 2003/6/1
Y1 - 2003/6/1
N2 - Imatinib mesylate is a selective Bcr-Abl kinase inhibitor, effective in the treatment of chronic myelogenous leukemia. Most patients in chronic phase maintain durable responses; however, many in blast crisis fail to respond, or relapse quickly. Kinase domain mutations are the most commonly identified mechanism associated with relapse. Many of these mutations decrease the sensitivity of the Abl kinase to imatinib, thus accounting for resistance to imatinib. The role of other mutations in the emergence of resistance has not been established. Using biochemical and cellular assays, we analyzed the sensitivity of several mutants (Met244Val, Phe311Leu, Phe317Leu, Glu355Gly, Phe359Val, Val379Ile, Leu387Met, and His396Pro/Arg) to imatinib mesylate to better understand their role in mediating resistance. While some Abl mutations lead to imatinib resistance, many others are significantly, and some fully, inhibited. This study highlights the need for biochemical and biologic characterization, before a resistant phenotype can be ascribed to a mutant.
AB - Imatinib mesylate is a selective Bcr-Abl kinase inhibitor, effective in the treatment of chronic myelogenous leukemia. Most patients in chronic phase maintain durable responses; however, many in blast crisis fail to respond, or relapse quickly. Kinase domain mutations are the most commonly identified mechanism associated with relapse. Many of these mutations decrease the sensitivity of the Abl kinase to imatinib, thus accounting for resistance to imatinib. The role of other mutations in the emergence of resistance has not been established. Using biochemical and cellular assays, we analyzed the sensitivity of several mutants (Met244Val, Phe311Leu, Phe317Leu, Glu355Gly, Phe359Val, Val379Ile, Leu387Met, and His396Pro/Arg) to imatinib mesylate to better understand their role in mediating resistance. While some Abl mutations lead to imatinib resistance, many others are significantly, and some fully, inhibited. This study highlights the need for biochemical and biologic characterization, before a resistant phenotype can be ascribed to a mutant.
UR - http://www.scopus.com/inward/record.url?scp=0038375012&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0038375012&partnerID=8YFLogxK
U2 - 10.1182/blood-2002-12-3659
DO - 10.1182/blood-2002-12-3659
M3 - Article
C2 - 12576318
AN - SCOPUS:0038375012
VL - 101
SP - 4611
EP - 4614
JO - Blood
JF - Blood
SN - 0006-4971
IS - 11
ER -