Abstract 392: Reverse functional genomics: Identifying differentially regulated functional networks as predictive biomarkers of pivotal vulnerabilities in pancreatic cancer

Pancreatic Ductal Adenocarcinoma (PDAC) is an incurable diseasecharacterized by poor survival, a dense desmoplastic stroma, and frequent activating mutations in KRAS( G12D inducible mouse lines. Refining this initial gene set for functional relevance, through parallel loss of function shRNA screens in orthotopic and 2D conditions, we were able to successfully define an in vivo enriched PDAC functional surfaceome. To interconnect each protein of the functional surface gene set, we utilized a protein-protein interaction dataset (STRING) and built a custom CRISPR sgRNA library for the purpose of informing the downstream oncogenicPDAC dependencies. Starting from oncogenicsignaling at the cell surface, we established a set of connected oncogenicmodules to functionally fingerprint each PDAC model both in vivo and in vitro. Our custom algorithm leveraging essentiality to define distinct oncogenicroutes has allowed insight into the shared core oncogenicdependencies within PDAC ( KRAS, MYC, etc), as well as model-specific central dependencies. Notably, many of the more central model-specific nodes, like AKT, EGFR, and UBC, were druggabletargets. These unique centralities have been confirmed through differential sensitivity to MK-2206, Gifitinib/ Erlotiniband AUY922 respectively. Importantly, by driving the defined network from periphery to center, we associated the unique pivotal dependencies to larger functional module sets to be leveraged as potential biomarkers. The functional modules suggested by the network and the associated vulnerability match the transcriptionally defined PDAC subtypes. To validate these module-based biomarker sets, we are currently leveraging a larger PDAC xenograft cohort, as well as patient data, to quantify the predictive capacity of the differentially regulated modules in the context of variable drug dependencies. Citation Format: Johnathon L. Rose, Alessandro Carugo, Wantong Yao, Sahil Seth, Sanjana Srinivasan, Michael Peoples, Traver Hart, Timothy Heffernan, Giulio Draetta. Reverse functional genomics: Identifying differentially regulated functionalnetworks as predictive biomarkers of pivotal vulnerabilities in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 392.