titutive pERK expression was significantly associated with higher WBC values and, most importantly, lower CR rates. Tortora et al. Page 13 Drug Resist Updat. Author manuscript, available in PMC 2008 September 23. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript GSK1904529A IGF-1R inhibitor Constitutive and functionally relevant activation of the MEK/ERK axis has been also recently reported in other haematological malignancies, including myelodysplastic syndrome , hairy cell leukaemia, and NK type lymphoproliferative disease of granular lymphocytes. 5.1. Preclinical activity of MEK inhibitors in haematological malignancies Collectively, the above reported data indicate that constitutive activation of the MEK/ERK MAPK module frequently occurs in human acute leukaemias, but not in normal haematopoietic progenitors, suggesting that it could be exploited for therapeutic purposes in haematopoietic malignancies.
Indeed, pharmacological MEK inhibitors, such as PD98059, GSK1363089 VEGFR inhibitor U0126, and CI 1040, have shown substantial growth inhibitory and pro apoptotic activity in vitro in both cell line models and primary samples of CML, AML , ALL, and MDS. In most studies, MEK inhibitor induced growth inhibition is due to a combination of inhibition of cell cycle progression and induction of apoptosis, which take place preferentially in cell lines and primary samples with high levels of constitutive ERK phosphorylation, but not in pERK negative leukaemias or CD34 haematopoietic progenitors from healthy donors.
The differential sensitivity of leukaemic cells with constitutive MEK/ERK activation to pharmacological MEK inhibitors has also been recently demonstrated both in vitro and in vivo in murine models of Raf 1 driven AML. More recently, we have analyzed the molecular and functional effects of the novel MEK inhibitor PD0325901 in cell line models of different haematopoietic malignancies : the growth of AML cell lines with known constitutive ERK activation was found to be exquisitely sensitive to MEK inhibition by PD0325901, with IC50s in the low nanomolar range. As mentioned above for other MEK inhibitors, growth inhibition was due to a combination of G1 cell cycle arrest and induction of apoptosis, which were also observed in response to PD0325901 in a substantial proportion of freshly isolated blasts from patients diagnosed with AML.
Genetic aberrations potentially resulting in the addiction of transformed cells to MEK activity were also explored in the murine FDC P1 model transfected with different oncogenes: in this model, constitutive activation of Fms, Ras, Raf, MEK, IGF 1R, and STAT5a conferred hypersensitivity to MEK inhibition, resulting in apoptosis induction at sub nanomolar concentrations of PD0325901. Phosphoprotein and gene expression profiling of OCI AML3 cells exposed to PD0325901 revealed extreme selectivity of the drug for its target and marked modulation of downstream targets, particularly genes and proteins involved in cell cycle regulation. Recent data obtained using ARRY 142886 indicate that MEK inhibition also induces potent growth inhibitory and pro apoptotic effects in vitro in multiple myeloma models, both cell lines and primary cultures in the presence or absence of bone marrow stromal cells. The effects are due, at least in part, to the downregulation of autocrine and paracrine cytokine loops and adhesion molecules mediating stromal cells, anti apoptotic activity. Interestingly, the expression of the c MAF oncogene, which is overexpress