nical development of such agents. However, information currently available Tortora et al. Page 12 Drug Resist Updat. Author manuscript, available in PMC 2008 September 23. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript does not allow to draw KU-55933 ATM inhibitor any definitive conclusion and biomarkers/predictive markers appear too premature to be the hinge driving MEK directed therapeutic programs forward at this time. 5. The MEK/ERK pathway as a therapeutic target in haematological malignancies Acute myeloid leukaemia is a deadly disease, resulting from the clonal expansion and accumulation of haematopoietic stem cells arrested at various stages of development.
Genetic aberrations that disrupt the function of haematopoietic BI 2536 755038-02-9 transcription factors play a central role in leukaemogenesis, in addition to transcription factor fusion proteins, aberrant activation of the kinase based signal transduction pathways that normally translate extracellular stimuli into appropriate homeostatic responses can powerfully contribute to leukaemogenesis by enabling leukaemic cells to grow autonomously and escape programmed cell death. A new paradigm is thus emerging, in which acute leukaemia could be modelled as comprising at least two mutational events: activation of a kinase based signaling pathway, which confers proliferative and/or anti apoptotic activity to haematopoietic cells without affecting differentiation, and a transcription factor fusion protein, which has a limited effect on cell transformation or proliferation, but impairs normal differentiation pathways.
The MAPK pathway that proceeds from Ras and its downstream effector Raf to MEK and ERK, is a key integration point along the signal transduction cascades that emanate from receptor and/or fusion protein associated tyrosine kinases and links diverse extracellular stimuli to proliferation, differentiation, and survival. We and others have recently provided substantial evidence that the MEK/ERK signaling module is frequently deregulated in myeloid leukaemias and other haematological malignancies, as a result of genetic and epigenetic aberrations involving both receptorassociated and cytoplasmic tyrosine kinases, as well as inhibitory phosphatases. Constitutive activation of this MAPK module is particularly common in AML, where ERK phosphorylation/activation is detected in primary leukaemic blasts in 50% to 90% of patients.
Conversely, constitutive ERK activation is usually not detectable in CD34 haematopoietic bone marrow progenitors from healthy donors or from leukaemic patients in complete remission. Most interestingly, from a clinical standpoint, both retrospective and prospective analyses of pERK levels in primary blasts obtained at diagnosis from AML patients indicate that high pERK levels are an independent predictor of worse overall survival, as a result of a combination of lower remission rates, shorter remission durations, and higher relapse rates. Limited information is available, at this time, on the presence and role of constitutive ERK signaling in acute lymphoblastic leukaemia. Constitutive ERK activation in ALL cell lines and in a limited number of clinical ALL specimens has been reported, together with suggestion that elevated pERK levels may be prognostic for survival. We have recently analysed constitutive ERK phosphorylation by flow cytometry in the largest series of primary adult ALL samples reported so far and found that approximately 30% of cases express pERK, cons