Abstract

Cancer therapy is challenged by the diversity of molecular implementations of oncogenic processes and by the resulting variation in therapeutic responses. Projects such as The Cancer Genome Atlas (TCGA) provide molecular tumor maps in unprecedented detail. The interpretation of these maps remains a major challenge. We have distilled thousands of genetic and epigenetic features altered in cancers to just a few hundred selected functional events (SFEs). Using this simplified description, we derived a hierarchical classification of thousands TCGA tumors from diverse cancer types. The top classes are dominated by either mutations (M class) or copy number changes (C class). This distinction is clearest at the extremes of genomic instability, indicating the presence of different oncogenic processes. The full hierarchy shows functional event patterns characteristic of multiple cross-tissue groups of tumors, termed oncogenic signature (OncoSign) classes. Targetable functional events in a tumor class are suggestive of class-specific combination therapy. These results may assist in the definition of clinical trials to match actionable oncogenic signatures with personalized therapies. I will also review our perturbation biology approach to the design of combinatorial therapy to overcome the emergence of resistance to targeted therapeutics, such as the RAF inhibitor in melanoma.