hat patients with constitutive activation of the MEK/ERK pathway are prospectively Danusertib Aurora Kinase inhibitor identified. Recent clinical data suggest that constitutive activation of multiple signaling pathways is the rule rather than the exception in AML, adding up to convey an increasingly adverse prognosis. However, the ability of MEK inhibitors to sensitize leukemic cells to apoptosis induced by a wide array of conventional and molecularly targeted anti cancer agents raises the hope that combinations with synergistic anti leukemic effects could be successfully developed for therapeutic purposes. Interestingly, the mechanism of action of certain combinations, such as the combination of MEK inhibitors and retinoids, appears to be entirely different from that of individual agents, suggesting that they may be usefully applied to patients potentially resistant to single pathway inhibition.
In summary, substantial progress has been made in the identification of molecular mechanisms of sensitivity/resistance XL147 956958-53-5 to targeted anti cancer agents and novel strategies to overcome resistance are being developed. Deeper insights into the molecular mechanisms of action of signal transduction inhibitors, alone or combined with other agents, and extensive preclinical/ early clinical modelling will be of paramount importance for the full realization of their therapeutic potential. Acknowledgements This work was support in part by grants from the Italian Ministry of Health, the Italian Association for Cancer Research, and the NIH USA.
Introduction In the United States, hepatoma is diagnosed in 19,000 patients per annum with 17,000 deaths from the disease, with a 5 year survival rate of less than 10%. Hepatoma is a leading cause of diagnosed cancer in Africa and Asia and represents the fifth most commonly diagnosed malignancy in the World. In the United States, pancreatic cancer is diagnosed in 37,000 patients per annum with 34,000 deaths every year. Pancreatic cancer has a 5 year survival rate of less than 5%. These statistics emphasize the need to develop novel therapies against these lethal malignancies. The Raf/mitogen activated protein kinase kinase 1/2 /extracellular signal regulated kinase 1/2 pathway is frequently dysregulated in neoplastic transformation, including hepatocellular carcinoma. The MEK1/2 ERK1/2 module comprises, along with c Jun NH2 terminal kinase and p38 MAPK, members of the MAPK super family.
These kinases are involved in responses to diverse mitogens and environmental stresses, including DNA damage, osmotic stress, and hypoxia, among others, and have also been implicated in multiple cellular functions, including proliferation, differentiation, and cell survival processes. Although exceptions exist, activation of the ERK1/2 pathway is generally associated with cell survival whereas induction of JNK1/2 and p38 MAPK pathways generally signals apoptosis. There is also evidence that the net balance of signals in terms of amplitude and duration between the cytoprotective ERK1/2 and the stressrelated JNK1/2 and p38 MAPK pathways determines whether a cell lives or dies following various insults. Although the mechanism by which ERK1/2 activation promotes survival is not known with certainty, several downstream anti apoptotic effector proteins have been identified, including direct inactivation of pro apoptotic proteins such as caspase 9, BAD and BIM, and increased expression of anti apoptotic proteins such as BCL XL, MCL 1 and c FLIP proteins. In view of the import