ERK2, but Not ERK1, Mediates Acquired and “De novo” Resistance to Imatinib Mesylate: Implication for CML Therapy

Clara I Aceves-Luquero,Eva M Galán Moya,Juan C Gómez,Anupriya Agarwal,Michael W Deininger,Azucena Esparís-Ogando,Laura Arias-González,Itxaso Bellón-Echeverria,Inmaculada Moreno Gimeno,Miguel A De La Cruz-Morcillo,Luis Del Peso Ovalle,Juan L Callejas-Valera,Ricardo Sánchez Prieto,Atanasio Pandiella

doi:10.1371/journal.pone.0006124

Abstract

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.

Highlights

Chronic Myeloid Leukaemia (CML) is one of the most studied human malignancies
To analyze the role of several members of the Mitogen Activated Protein Kinases (MAPKs) family in the acquired resistance to Imatinib Mesylate (IM) we used two cell lines, K562 and Lama84, and their resistant derivates generated by co-culturing with IM [13]
This set of experiments indicates that in our experimental system resistance correlates with an increase in Bcr/Abl expression level and excludes mutations in the ATP binding site

Summary

Introduction

The disease is originated in a hematopoietic stem cell progenitor by a reciprocal translocation between chromosome 9 and 22 t(9:22)(q34:11) joining the c-ABL tyrosine kinase on chromosome 9, and the Break point Cluster Region (BCR) on chromosome 22 This generates a chimeric protein with deregulated activity, which plays an essential role in the pathogenesis of the disease (for review see [1]). Futhermore, IM has been reported to fail to control disease progression in the absence of BCR/ABL mutations, an aspect that remains poorly understood [9,10] Several mechanisms, such as the overexpression of Bcr/ Abl, increases in drug efflux transport proteins or the overexpression of other members of the Src tyrosine kinase family have been proposed to explain the failure to respond to IM (for a review [11]). De novo and acquired resistance to IM in CML seem to have a convergence point in the Bcr/Abl overexpression, which is a common feature of the two last phases of the disease [15,16,17]

Objectives

Methods

Results

Conclusion