ed in approximately 50% of MM, and its downstream targets integrin 7, CCR1, and cyclin D2, were profoundly downregulated by ARRY 142886 in MM models exposed to hypoxia and/or IL 6. Overall, these results strongly support the hypothesis that constitutive ERK activation in AML blasts is crucial to Tortora et al. Page 14 Drug Resist Updat. Author manuscript, available in PMC 2008 September 23. PF-04217903 c-Met inhibitor NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript their ability to proliferate and survive default apoptosis induction in the absence of specific survival factors or in response to death stimuli. Not only is this constitutive activation crucial, but it also confers a high sensitivity to inhibitors of the MEK/ERK pathway that could be exploited for therapeutic purposes.
Conversely, recent data indicate that in normal haematopoietic progenitors the activation of the MEK/ERK XL880 c-Met inhibitor module is not only dispensable for expansion, proliferation and self renewal, but could rather mark the transition from proliferation to maturation, thereby limiting the proliferative potential of self renewing stem cells and thus providing the basis for a highly selective anti leukaemic activity of MEK inhibitors. 5.2. Prospects for MEK inhibition based combinations with synergistic anti leukaemic activity Although exceptions occur, the bulk of evidence indicates that constitutive activation of the MEK/ERK signaling module increases the apoptotic threshold of leukaemic and other cancer cells, consistent with its ability to regulate the expression and function of multiple antiapoptotic players through transcriptional and non transcriptional mechanisms.
In particular, MAPK signaling may favour cell survival both at the mitochondrial level, through regulation of the expression and function of pro and anti apoptotic Bcl 2 family members, and at the cytosolic caspase activation level, through regulation of the expression of caspase inhibitors of the IAP family and the recently described direct phosphorylation and inactivation of pro caspase 9. However, at concentrations close to the IC50 for ERK enzymatic activity, MEK inhibitors have cytostatic rather than cytotoxic effects and higher doses are required to efficiently trigger apoptosis, suggesting that other parallel cytoprotective pathways that help maintain cell viability may be operative in cancer cells.
Nevertheless, one of the most intriguing features of MEK inhibitors as potential anti cancer agents is their ability to lower leukaemic cells, apoptotic threshold, setting the stage for increased sensitivity to the pro apoptotic action of classical cytotoxic drugs, ionizing radiation, and other biological agents that modulate apoptosis. Together with their amenability to pharmacodynamic evaluation and negligible systemic toxicity, these apoptosis sensitizing actions make MEK inhibitors an ideal starting point to build pharmacological combinations with synergistic antileukaemic effects. 5.3. MEK inhibition based combinations with cytotoxic agents Several lines of evidence indicate that the activity of the MEK/ERK module may be particularly critical in regulating chemosensitivity in leukaemic cells. Consistent with a cytoprotective action of the MEK/ERK pathway, MEK blockade by pharmacological inhibitors, strikingly increases Ara C cytotoxicity, at least in part through enhanced cytosolic release of cytochrome c and Smac/DIABLO, but not loss of mitochondrial membrane potential, thereby implicating activation o