Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia.
Imatinib mesylate (IM) binds to the BCR-ABL protein, inhibiting its kinase activity and effectively controlling diseases driven by this kinase. IM resistance has been associated with kinase mutations or increased BCR-ABL expression. However, disease progression may be mediated by other mechanisms that render tumor cells independent of BCR-ABL. To demonstrate this potential, IM-resistant cells were found in chronic myelogenous leukemia patients with continuous BCR-ABL gene expression but undetectable BCR-ABL protein expression. These cells were unresponsive to IM and acquired BCR-ABL-independent signaling characteristics. IM resistance in some patients may be mediated through loss of kinase target dependence.
Donato
Nicholas J
NJ
Department of Bioimmunotherapy, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ndonato@mdanderson.org
Wu
Ji Y
JY
Stapley
Jonathan
J
Lin
Hui
H
Arlinghaus
Ralph
R
Aggarwal
Bharat B
BB
Shishodia
Shishir
S
Albitar
Maher
M
Hayes
Kimberly
K
Kantarjian
Hagop
H
Talpaz
Moshe
M
Shishodin
Shishir
S
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D017403:In Situ Hybridization; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D020079:Terminal Repeat Sequences / Q000235:genetics
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl