Treating Cancer by Blocking Cell Signals

Cancer development and propagation occur through defects inside and outside the cancer cell. Extracellular events occur in the stroma and vasculature. A central role in dysregulated cell function is attributed to signaling systems. In multicellular organisms, a diverse array of growth factors, cytokines, and proto-oncogenes transduce their growth-promoting signals through the activation of phosphor-relay modules. These modules, composed of protein kinases, transduce signals from the cell surface to the nucleus, leading to gene transcription and the activation of myriad metabolic processes. Cell signaling is tightly controlled for normal cell functioning, and dysregulation of this system through genetic alterations can lead to the malignant phenotype of uncontrolled proliferation, inhibition of apoptosis, metastasis, and angiogenesis. Protein kinases play a central role in dysregulated cell signaling. In particular, two pathways have been found to be critical for maintenance of the malignant phenotype. The lipid kinase phosphoinositide 3-OH kinase (PI3K) pathway and its downstream targets, such as the protein-serine/threonine kinases Akt and p70 S6 kinase (p70), are crucial effectors in oncogenic signaling, as is the Ras-Raf-MAP (mitogen-activated protein) kinase pathway. Due to cross talk between signaling pathways, these two signaling modules are inter-related rather than linear, and they interact with important cytoplasmic protein kinases (of which at least 32 have been described) such as bcr-abl, src, and JAK/STAT (Janus kinase/signal transducer and activators of transcription). The central role of protein kinases in oncogenesis makes these molecules attractive targets for cancer therapy. However, despite the wealth of potential targets, the most advanced compounds currently on the market or in clinical development target only a handful of the bestcharacterized kinases. The modulation of kinase activity can be achieved through several strategies: blocking of circulating ligand, inhibition of ligand binding to extracellular components of membrane receptors, inhibition of phosphorylation activity by blocking adenosine triphospage (ATP) binding, disruption of protein-protein interactions, and downregulation of kinase gene expression by antisense or RNA interference approaches. Blocking of circulating ligand and inhibition of ligand binding to membrane receptors have been achieved through the use of monoclonal antibodies, and represent a successful strategy, as evidenced by the approval of trastuzumab, bevacizumab, and cetuximab for a number of solid tumor indications. While the inhibition of intracellular signaling represents an opportunity for the design of multiple approaches, the inhibition of ATP binding to the kinase domain of multiple proteins appears to be the most druggable strategy, and represent the only successful approach to date, as evidenced by the approvals of imatinib, gefitinib, and erlotinib for various indications. A problem that has emerged with this approach is the emergence of resistance due to specific mutations in these kinase domains. This issue reviews a number of these agents in clinical trials. Platelet derived growth factor receptor alpha mutations in a panel of more than 1,000 gastrointestinal stromal tumors and their relationship to imatinib sensitivity have been elegantly described. A phase I study of the first-generation MEK (MAP kinase– extracelluar receptor kinase [ERK]) inhibitor CI-1040 is presented here. Although the development of this agent has been discontinued because of poor pharmacologic properties, two second-generation agents in this class are currently undergoing clinical testing. Multikinase inhibitors are undoubtedly attracting attention currently. A number of these are highlighted in Table 1. The initial phase I studies of the dual HER1/HER2 kinase inhibitor, lapatinib is reported in this volume. Finally, several studies of the mammalian target of rapamycin (mTOR) inhibitor CCI-779 are presented here. This illustrates the pivotal role of the Akt-mTOR axis in malignant cell survival and apoptosis, as well as its role in transducing signals from VOLUME 23 d NUMBER 23 d AUGUST 1