• hepatocellular carcinoma

Treatment options for advanced hepatocellular carcinoma (HCC) are limited. Although some multikinase inhibitors such as sorafenib show some benefit, this does not significantly alter the course of disease for most patients. Currently, several multikinase inhibitors were shown to work in first-line or second-line treatments, but the overall benefit is quite small. Thus, we urgently need to find ways to increase response rates and perhaps more important, to be able to sustain responses for longer periods.1 Chemotherapy combinations changed the history of cancer therapy when first introduced in childhood malignancies and such combinations remain the main treatment option for many cancer patients. Some kinase inhibitors were also shown to work better in combination—for example, the combination of B-RAF and MEK inhibitors in advanced melanoma showed significantly improved rates of progression-free and overall survival versus B-RAF inhibition alone.2 The choice of the combination in this case was made based on preclinical data suggesting that MEK activation is a major determinant of progression in vemurafenib (a B-RAF-inhibitor) treated melanomas. In the absence of clear cut mechanisms of acquired resistance to sorafenib (which is a multikinase inhibitor), how can we find drug combinations which will increase its efficacy?

One way to search for therapeutic targets is the loss of function …