VEGFR, PDGF and Raf in endothelial and tumour cells may induce BMY 7378 5-HT receptor antagonists and agonists a strong simultaneous antiangiogenic effect. In preclinical studies, the combination of gefitinib with sorafenib resulted in tumour growth inhibition of A549 NSCLC xenografts with almost no toxicity. A phase I study on the combination of gefitinib and sorafenib has been conducted in patients affected by metastatic NSCLC. Among 30 evaluable patients, one partial response and 20 disease stabilizations were observed, with a median duration of 20.4 weeks . The treatment was well tolerated, the most common drug related adverse events being diarrhoea, fatigue and transaminase elevation. This combination strategy is now under further evaluation. 4.
The MAPK pathway Approximately twenty years after their initial discovery, at least JNJ 26854165 881202-45-5 four major MAPK families have been identified in mammalian cells: extracellular signal regulated kinase, c Jun N terminal kinase 1/2/3, p38//γ/δ, and ERK 5. They exert specific, albeit crosstalking, roles in the regulation of fundamental cellular functions. A detailed description of molecular themes underlying MAPK activation and function is beyond the scope of this review and has been covered by other recent overviews. Briefly, the basic MAPK module consists of three protein kinases that are sequentially activated by a phosphorylation cascade: a MAPK kinase kinase, a MAPK kinase, and a MAPK. A high degree of redundancy and overlap occurs upstream of MAP3K activation and the existence of a plethora of MAP3Ks reflects the exceptional variety of signals capable of recruiting these pathways, usually in combinatorial arrays.
However, specificity progressively increases as signal transduction proceeds, so that little or no crosstalk exists between different modules at the MAPK level. Among the different MAPK modules, the Raf/MAPK/ERK kinase /ERK is the most extensively studied and perhaps the most relevant to cancer pathogenesis and therapy. This signaling module is activated by several extracellular stimuli that converge on the small G protein Ras. It plays a Tortora et al. Page 8 Drug Resist Updat. Author manuscript, available in PMC 2008 September 23. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript pivotal role in the control of cell proliferation, differentiation, and survival in response to the engagement of receptor tyrosine kinases, G protein coupled receptors, and integrins.
Activated Ras, in turn, recruits the MAP3K Raf to the plasma membrane in a necessary, but not sufficient, activation step, allowing the mitogenic signal to proceed through the MEK/ERK module. MEK activation is a crucial step in signal transduction through the Raf/MEK/ERK cassette: MEK 1/2 belong to a small family of dual specificity kinases and catalyze the phosphorylation of ERK on both Ser/Thr and Tyr residues, allowing their full activation. This activation step is endowed with extremely high specificity, in that MEK is the only ERK kinase and ERK is the only MEK substrate identified thus far. Such high specificity has made MEK activation and enzymatic activity a prime target for pharmacological interventions directed against this MAPK module. ERK is the dominant multifunctional effector of the MAP3K/MAP2K/MAPK cassette: it directly phosphorylates many transcription factors including Ets 1, c Jun, and c Myc, phosphorylates and activates the 90 kDa ribosomal S6 kinase, leading to the activation of the transcription factor CREB, phosphorylates many prot