Abstract A029: AI-Driven Network-Based Discovery on TCGA-PAAD Identifies KRAS-Axis Drug-Repurposing Targets for Pancreatic Cancer Interception
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common cancer (5-year survival ∼13%), emerging through years-to-decades progression involving chronic fibro-inflammatory injury and precursor transformation processes including ADM and PanIN. KRAS-driven acinar-to-ductal metaplasia (ADM) is among the earliest experimentally tractable and potentially interceptable events; KRAS (mutated in >90% of PDAC) has remained difficult to therapeutically target, particularly for prevention; emerging KRAS inhibitors are developed for treatment of established malignancy rather than early interception. We aimed to prioritize KRAS-axis interception candidates via AI-guided network analysis of TCGA-PAAD restricted to a curated KRAS-driven ADM/PanIN-initiation mechanism module. The 38-gene module (n=183 TCGA-PAAD samples; 37 genes available, PRSS2 absent) spans KRAS-MAPK, RTKs, TGF-β/SMAD, ECM, inflammation, transcription, tumor suppressors, and ductal/acinar genes from canonical pancreatic-cancer-progression biology, linking established-tumor transcriptomes to early-interception biology. A stability-selected Spearman-correlation network served as the network backbone (PCMCI+/NOTEARS extensions ongoing), paired with patient-level bootstrap filtering (B=200 resamples; ≥70% retention). A composite Interception Score I(v) = α·CB + β·Σ|w| + γ·U + δ·R integrating betweenness centrality, summed edge-weight influence, druggability (literature-curated drug-target prior), and bootstrap robustness ranked candidate interception nodes (unoptimized weights; tuning ongoing). Spearman correlation yielded a 37-node, 248-edge network baseline; bootstrap resampling (B=200) evaluated 856 distinct candidate edges, of which 194 (22.7%) achieved ≥70% retention, defining the stable subgraph used for scoring. The Interception Score placed 7 KRAS-axis genes among the top-10 candidates: ERBB2 (0.953), KRAS (0.743), ERBB3 (0.742), MAPK1 (0.708), EGFR (0.675), MAP2K2 (0.605), and BRAF (0.589). Inflammation (IL6, 0.755), TGF-β/SMAD2 (0.726), and ECM/MMP2 (0.638) also ranked highly, recapitulating PDAC initiation mechanisms (stromal-epithelial crosstalk; inflammatory-fibrotic priming). ERBB2 (HER2), a clinically druggable RTK with approved inhibitors in other malignancies, emerged as the top-ranked candidate, supporting evaluation of HER2-axis signaling for interception in molecularly selected PDAC subsets. These findings align with canonical PDAC biology, supporting biological plausibility prior to formal weight optimization and external validation. AI-guided network analysis of TCGA-PAAD prioritizes biologically coherent KRAS-axis and stromal-inflammatory candidates with clinically available HER2-, EGFR-, MEK-, BRAF-, and KRAS-pathway inhibitors, supporting hypothesis generation for future pancreatic cancer interception studies. Stage-resolved analysis, causal-inference extensions, and sex-/age-stratified validation are ongoing. Jianfu Li, Yingyun Yang, Michael Wallace, Cui Tao, Yan Bi. AI-Driven Network-Based Discovery on TCGA-PAAD Identifies KRAS-Axis Drug-Repurposing Targets for Pancreatic Cancer Interception [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A029.