The long-term goal of Sellers lab is to deeply investigate cancer dependent genes to inform therapeutic discovery in cancer. The approaches to this problem have taken three forms. First, while at the Dana-Farber Cancer Institute and Broad Institute, together with Matthew Meyerson we pioneered genome scale approaches to the discovery of genetic alterations in cancer (Paez et al. Science 2004, Garraway et al. Nature. 2005). Second, while at the Novartis Institutes for Biomedical Research the groups I led developed large-scale model systems for interrogating functional perturbations in cancer including the Cancer Cell Line Encyclopedia (Barretina et. al. Nature 2012) and the Primary tumor Derived Xenograft Encyclopedia (Gao et. al. Nat Med. 2015). The CCLE, in turn, was the foundation for the conduct of large-scale discovery screens employing pooled shRNA libraries to uncover novel vulnerabilities in cancer. These experiments led to the notable discovery of novel synthetic lethal interactions between depletion of hBRM and mutations in BRG1 in NSCLC, and between genetic deletion of the MTAP and a specific dependence on the arginine methyltransferase PRMT5 (Mavrakis et al. Science 2016). Third, the direct discovery of therapeutics targeting novel domains and pockets unveiling both new ways to tackle validated cancer dependent genes, and elucidating new ways to overcome therapeutic resistance (Chen et al. Nature 2016, Wylie et al. Nature 2017).

In the Sellers laboratory at the Broad Institute we are continuing systematic efforts to perturb cancer cells beyond single gene knockout experiments. Approaches to refining the problem of understanding cancer gene function including CRISPR tiling, systematic direct mutagenesis and the development of new protein perturbation methods are being deployed in aggregate to discover new mechanisms of cancer dependence. Therapeutically tractable hypothesis developed in the laboratory have the opportunity to progress to drug discovery efforts in collaboration with the Center for the Development of Therapeutics at the Broad.