Abstract PR04: Cooperation between Ras network mutations in cancer

Cancer genome sequencing often identifies mutations within the Ras signaling network other than the well-established KRAS, NRAS, and BRAF oncogene mutations and NF1 tumor suppressor gene mutations. The extent to which a novel mutation in a commonly mutated pathway can be assumed to have cancer promoting potential, and whether or not certain contextual conditions are required for the mutation to have cancer promoting effects, is not well understood. We investigated this problem with a computational model of the Ras signaling network, with focused cell-based experiments, and with statistical analysis of large cancer genomic data sets. We first applied our previously developed computational model of the Ras signaling network to identify potential synergistic combinations within the Ras network. For example, our modeling suggested that mutations to the tumor suppressor gene NF1 can amplify the effects of other Ras pathway mutations, including the effects of weakly-activating, noncanonical, Ras mutants. Experiments comparing the strength of signal produced by noncanonical Ras mutants expressed in neurofibromin deficient and wild-type cells confirmed this prediction. If such synergistic effects contribute to the development of cancer, we reasoned that there should be an increased rate of co-occurrence between the mutations that the model predicted to have cooperative potential. Analysis of large cancer genomic data sets from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas identified increased rates of co-occurrence between mutations predicted to display synergy. Overall, our study suggests that there may be combinations of Ras pathway mutations that serve the role of cancer “driver”. This abstract is also presented as Poster B33. Citation Format: Edward C. Stites, Paul C. Trampont, Lisa B. Haney, Scott F. Walk, Kodi S. Ravichandran. Cooperation between Ras network mutations in cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr PR04. doi: 10.1158/1557-3125.RASONC14-PR04