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

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.

Forced Expression of Cyclin-Dependent Kinase 6 Confers Resistance of Pro-B Acute Lymphocytic Leukemia to Gleevec Treatment

“…The absence of any effects on E2A in A-MuLV-transformed cells in the presence of a MEK inhibitor suggests that two different pathways are regulating the induction and the repression of Cdk6 transcription. Interestingly, it has been observed that ERK2 and not ERK1 mediates resistance to STI571 in BCRAbl leukemic cells (1). This demonstrates that the Erk pathway drives proliferation in Abl-transformed cells, but our finding shows that ERK1 is important in v-Abl-transformed cells.…”

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

“…86 Erk2, but not Erk1, activation may also potentiate the development of imatinibresistance. 87 Activation of the Janus kinase (Jak) and subsequent phosphorylation of several Signal Transducer and Activator of Transcription (STAT) family members has been identified in both Bcr-Abl-positive cell lines and in primary CML cells and may contribute to the transforming ability of Bcr-Abl. 88,89 Epigenetic modification Gene expression and subsequent protein function can be governed by a balance of epigenetic methylation, as well as post-translational acetylation, respectively.…”

Molecular pathogenesis of tyrosine kinase resistance in chronic myeloid leukemia

“…In our own laboratory, we found excessive activation of the MAP kinases (MAPKs) Erk1/Erk2 in response to TKI treatment, further supporting the notion that TKI treatment of T315I-positive CML might increase oncogenic fitness of mutant T315I beyond the TKI-naive oncogenic potential. MAPKs represent a signaling cascade able to circumvent BCR-ABL-targeted therapy, thereby promoting resistance in preclinical models [16,17]. These data add novel mechanistic explanations supporting the clinical recommendation to discontinue TKI treatment when high resistance mutations are detected not only to allow deselection of the mutant clone, but also to prevent TKI-dependent acceleration of progressive disease.…”