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.

c-Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin-based therapy.

Activation of p38 MAPK is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. In this sense, a growing body of evidences supports the role of c-Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c-Abl. Indeed, c-Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c-Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia-derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c-Abl overexpression on p38 MAPK activation. These findings may explain why a clinically used c-Abl inhibitor, imatinib mesylate, fails to inhibit the p38 MAPK pathway alone or in combination with cisplatin, and provide evidence of a novel signaling mechanism in which these antitumor agents act.