New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors.

Signal transduction in cancer cells is a sophisticated process that involves receptor tyrosine kinases (RTKs) that eventually trigger multiple cytoplasmic kinases, which are often serine/threonine kinases. A number of tumor models have identified several key cellular signaling pathways that work independently, in parallel, and/or through interconnections to promote cancer development. Three major signaling pathways that have been identified as playing important roles in cancer include the phosphatidyl inositol-3-kinase (PI3K)/AKT, protein kinase C (PKC) family, and mitogen-activated protein kinase (MAPK)/Ras signaling cascades. In clinical trials, highly selective or specific blocking of only one of the kinases involved in these signaling pathways has been associated with limited or sporadic responses. Improved understanding of the complexity of signal transduction processes and their roles in cancer has suggested that simultaneous inhibition of several key kinases at the level of receptors and/or downstream serine/threonine kinases may help to optimize the overall therapeutic benefit associated with molecularly targeted anticancer agents. Using targeted agents to inhibit multiple signaling pathways has emerged as a new paradigm for anticancer treatment based on preclinical and clinical data showing potent anti-tumor activity of single drugs inhibiting multiple molecular targets or combination therapies involving multiple drugs with selective or narrow target specificity. Preclinical and clinical studies point to molecules on vascular endothelial cells and pericytes as being important targets for anticancer therapies, as well as molecules on or within tumor cells themselves. This suggests that optimal therapeutic approaches to cancer may involve targeting multiple molecules found in both the tumor and supportive tissues. In this review, we will use the most recent preclinical and clinical data to describe this emerging paradigm for anticancer therapy involving targeting multiple signaling pathways with tyrosine or serine/threonine kinase inhibitors.

Differential protein expression, DNA binding and interaction with SV40 large tumour antigen implicate the p63-family of proteins in replicative senescence.

P53 activity plays a key role in mammalian cells when they undergo replicative senescence at their Hayflick limit. To determine whether p63 proteins, members of the family of p53-related genes, are also involved in this process, we examined their expression in serially passaged rat embryo fibroblasts. Upon senescence, two truncated DeltaNp63 proteins decreased in abundance whereas two TAp63 isoforms accumulated. 2-D gel analysis showed that the DeltaNp63 proteins underwent post-translational modifications in both proliferating and senescent cells. Direct binding of DeltaNp63 proteins to a p53 consensus motif was greater in proliferating cells than senescent cells. In contrast p63alpha isoforms bound to DNA in a p53 dependent manner and this was higher in senescent cells than proliferating cells. An interaction of p63alpha proteins with SV40 large tumour antigen was also detected and ectopic expression of DeltaNp63alpha can extend the lifespan of rat embryo fibroblasts. Taken together the results indicate that p63 proteins may play a role in replicative senescence either by competition for p53 DNA binding sites or by direct interaction with p53 protein bound to DNA.