Anti-cancer drugs targeting protein kinases include small molecule inhibitors and monoclonal

Anti-cancer drugs targeting protein kinases include small molecule inhibitors and monoclonal antibodies. of protein IKBKB kinases in cancer cells is extremely common. Consequently protein kinases are attractive targets for anti-cancer drugs including small molecule inhibitors which usually act to block binding of ATP Flumazenil or substrate to the catalytic domain of the tyrosine kinase (TK) and monoclonal antibodies which specifically target receptor tyrosine kinases (RTKs) and their ligands. The most exquisite example of successful targeted therapy is perhaps that of imatinib designed specifically to target an abnormal constitutively active BCR-ABL Flumazenil tyrosine kinase found in >90% of cases of chronic myeloid leukaemia (1). In solid malignancies it is unusual for a single kinase abnormality to be the sole cause of disease and it is unlikely that tumours are dependent on only one abnormally activated signalling pathway. Instead multiple signalling pathways are dysregulated. Furthermore even single molecular abnormalities may have multiple downstream effects. Thus unless it is possible to target a single key underlying defect it is likely that therapies will be more effective by inhibiting a number of downstream targets. Advantages of such a ‘multi-targeted’ approach include the potential for increased efficacy and reduced resistance by simultaneous inhibition of multiple pathways and common escape pathways. Disadvantages include possible increased cost and toxicity. Another important question is whether simultaneous or sequential administration of targeted drugs produces superior efficacy. The theoretical background for simultaneously targeting multiple targets is not the same as simultaneously using multiple agents. Employing sequential use of non-cross resistant therapies may in some cases result in improved outcomes. Importantly even agents with similar modes of actions such as sunitinib and sorafenib appear to demonstrate a rather low level of cross-resistance as demonstrated by two clinical trials comparing the sequential use of sunitinib and sorafenib and vice versa(2 3 Sequential therapy may also be associated with a more favourable toxicity profile but ultimately this is a question which will need to be resolved in clinical trials. Multiple pathways can be targeted either by using a single agent which inhibits multiple signalling pathways or by using a combination of highly selective agents. While use of a single multi-targeted agent offers convenience potential limitations include difficulties in obtaining sufficient potencies against multiple targets in tumour cells without excessive toxicity from cross-reactivity with normal tissues. Differing affinities for the receptors may result in relatively greater inhibition of one target to achieve adequate inhibition of another resulting in toxicity. In contrast combining selective agents with the aim of achieving additive or synergistic effects may allow high target selectivity with reduced systemic effects though this is at the risk of potential pharmacodynamic and pharmacokinetic interactions between the drugs. Ideally combination therapies should use effective agents with differing mechanisms of action and adverse effect profiles. In this review we discuss the principles of specifically targeting multiple kinase pathways. Angiogenic Signalling Pathways Angiogenesis is crucial for tumour progression and metastasis and is increasingly a target for cancer therapies. Flumazenil The vascular endothelial growth factor (VEGF) family of proteins consist of numerous subtypes including VEGF-A VEGF-B VEGF-C VEGF-D VEGF-E and placenta-growth Flumazenil factor-1(reviewed within(4)) most of which bind to cell membrane-associated RTKs the VEGF-receptors (VEGFRs). The binding of VEGF ligand to Flumazenil its receptor initiates activation of downstream signalling pathways including the RAF-MEK-ERK and PI3K pathways which ultimately lead to endothelial cell activation proliferation migration and survival (Figure 1a). Increased VEGF expression is found in a variety of human tumours including colorectal cancer (CRC) non-small cell lung cancer (NSCLC) breast and ovarian cancers and is correlated directly with increased neovascularisation within the tumour (reviewed in (5)). Drugs targeting the VEGF pathways include the monoclonal antibody bevacizumab and the.