ERK2, but not ERK1, mediates acquired and "de novo" resistance to imatinib mesylate: implication for CML therapy.
Resistance to Imatinib Mesylate (IM) is a major problem in Chronic Myelogenous Leukaemia management. Most of the studies about resistance have focused on point mutations on BCR/ABL. However, other types of resistance that do not imply mutations in BCR/ABL have been also described. In the present report we aim to study the role of several MAPK in IM resistance not associate to BCR/ABL mutations. Therefore we used an experimental system of resistant cell lines generated by co-culturing with IM (K562, Lama 84) as well as primary material from resistant and responder patient without BCR/ABL mutations. Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype. However, Erk2, but not Erk1, is critical for the acquired resistance to IM. In fact, Bcr/Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c-Abl part of the chimeric protein. Finally, we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM. In summary our data support the use of therapeutic approaches based on Erk2 inhibition, which could be added to the therapeutic armamentarium to fight CML, especially when IM resistance develops secondary to Erk2 activation.
Aceves-Luquero
Clara I
CI
CRIB/Facultad de Medicina, UCLM, Albacete, Spain.
Agarwal
Anupriya
A
Callejas-Valera
Juan L
JL
Arias-González
Laura
L
Esparís-Ogando
Azucena
A
del Peso Ovalle
Luis
L
Bellón-Echeverria
Itxaso
I
de la Cruz-Morcillo
Miguel A
MA
Galán Moya
Eva M
EM
Moreno Gimeno
Inmaculada
I
Gómez
Juan C
JC
Deininger
Michael W
MW
Pandiella
Atanasio
A
Sánchez Prieto
Ricardo
R
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D017354:Point Mutation; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3