In vivo RNAi screening for novel therapeutic cancer targets


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Daniel Peeper1
1Netherlands Cancer Institute, Amsterdam, The Netherlands

Abstract

Melanoma is the most aggressive type of skin cancer and its incidence is steadily increasing. Melanomas tend to spread rapidly, which is associated with a grim prognosis. Until recently, most advanced stage melanomas were refractory to the available therapeutic options, but there are recent developments offering better perspectives. For example, new therapeutic approaches have become available, which target genetic vulnerabilities within the melanomas. A primary example of such a dependency is the common BRAFV600E mutation, which is essential for proliferation and survival of melanoma cells. In the clinic, the mutant BRAF oncogene product can be targeted by specific inhibitors, including vemurafenib, which cause unprecedented melanoma regression. However, relapse eventually occurs around six months due to a variety of resistance mechanisms, both MAP kinase-dependent and -independent. Therefore, in spite of these new perspectives, there is a dire need to identify additional targets amenable to therapeutic intervention, to be used in combination with vemurafenib or other specific inhibitors to overcome or prevent drug resistance and achieve more durable responses. To achieve this, we set out to identify melanoma factors that are required for proliferation and survival specifically in an in vivo setting. Thus, we performed negative selection RNAi screens parallel in vitro and in vivo and focused on the hits that were preferentially depleted in tumours relative to the corresponding cells in culture. The results from these screens will be discussed.