Abstract A09: Decomposing Oncogenic Transcriptional Signatures to Generate Maps of RAS/MAPK Cellular States

The systematic sequencing of the cancer genome has provided a powerful framework for identifying genetic alterations in cancer. However, a deeper understanding of the functional consequences of these alterations is necessary to guide appropriate therapeutic strategies. Here, we describe Onco-GPS (OncoGenic Positioning System), a data-driven analysis framework, and associated experimental and computational methodology, to organize individual tumor samples with shared oncogenic alterations onto a reference map defined by their underlying cellular states. Using this approach, we generated series of RAS/MAPK sub-signatures that reflect known and novel downstream pathways. These sub-signatures were then used to classify KRAS and BRAF mutant cancers into sub groups or cell states, as represented in the novel visual paradigm OncoGPS map. The approach not only accurately classified three groups of BRAF mutant cancers that aligned with sensitivity to BRAF inhibitors, but also identified resistance mechanisms associated with each state. OncoGPS also identified four major cell states associated with KRAS mutant cancers. Further characterization of the four cell states showed that multiple molecular features representing epithelial-EMT states and activation of NF-B pathway delineated two major axes of KRAS mutant cancers. In addition to the pathways and cell states defined in each group, the OncoGPS approach is able to identify effective drug combinations which was experimentally tested ...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: New Technology and Bioinformatics: Poster Presentations - Proffered Abstracts Source Type: research