TY - JOUR
T1 - ERK2, but not ERK1, mediates acquired and "De novo" resistance to imatinib mesylate
T2 - Implication for CML therapy
AU - Aceves-Luquero, Clara I.
AU - Agarwal, Anupriya
AU - Calllejas-Valera, Juan L.
AU - Arias-González, Laura
AU - Esparís-Ogando, Azucena
AU - Ovalke, Luis del Paso
AU - Bellón-Echeverria, Itxaso
AU - de la Cruz-Morcillo, Miguel A.
AU - Moya, Eva M.Galán
AU - Gimeno, Inmaculada Moreno
AU - Gómez, Juan C.
AU - Deininger, Michael W.
AU - Pandiella, Atanasio
AU - Prieto, Ricardo Sánchez
PY - 2009/7/1
Y1 - 2009/7/1
N2 - 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. cr 2009 Aceves-Luquero et al.
AB - 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. cr 2009 Aceves-Luquero et al.
UR - http://www.scopus.com/inward/record.url?scp=67651241759&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67651241759&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0006124
DO - 10.1371/journal.pone.0006124
M3 - Article
C2 - 19568437
AN - SCOPUS:67651241759
SN - 1932-6203
VL - 4
JO - PloS one
JF - PloS one
IS - 7
M1 - e6124
ER -