A Shared Adenocarcinoma Transcriptomic Program Enables Prediction of Therapeutics Applicable Across Tissues

Abstract

BackgroundAdenocarcinomas are malignancies arising from glandular epithelial cells or secretory tissue, and account for most cancer-related mortalities worldwide, despite advances in treatment. New treatments are often developed in the context of the organ from which the tumor originates. However, there exists shared biology across glandular epithelium at the molecular level regardless of organ system, and there has been a shift towards the molecular classification of tumors. Defining and targeting pan-adenocarcinoma specific molecular features may facilitate the development of treatments applicable across adenocarcinomas, expediting drug discovery efforts and translation to the clinical setting. MethodsWe performed an integrated transcriptomics analysis of adenocarcinomas originating from different organ systems. RNA sequencing expression profiles from lung adenocarcinoma (LUAD), stomach adenocarcinoma (STAD), and colorectal adenocarcinoma (COAD) with matched normal tissue from The Cancer Genome Atlas (TCGA) was used to discover a pan-adenocarcinoma specific transcriptomic module. A standardized DESeq2 based pipeline was used to test for differentially expressed genes (DEGs) between each adenocarcinoma and its matched normal tissues, followed by cross-cancer comparisons to identify a consensus transcriptional module. Enrichment analysis was performed to reveal biological pathways associated with the consensus module, with a particular focus on those involved in oncogenesis. Prognostic significance of the consensus transcriptional module was evaluated using survival modeling, and the module was tested against in vitro transcriptomic drug perturbation signatures using Connectivity Map (cMAP) analysis to identify candidate drugs targeting adenocarcinomas, regardless of organ system of origin. ResultsDespite the diversity of adenocarcinomas tested, there existed a significant and large overlap of the genes dysregulated across tested tumors. A consensus transcriptomic module was defined, and it predicted patient prognosis in each of the three adenocarcinomas. Leveraging the top shared biomarkers through cMAP analysis, we identified 36 FDA-approved drugs that are capable of reversing the shared malignant transcriptional module towards the normal state. Among the FDA-approved drugs were the EGFR and ALK inhibitors gefitinib and crizotinib, both currently used for treating LUAD, providing validation the pipeline could discover efficacious drugs. Taken together, we developed an approach for organ system independent cancer biomarkers and drug discovery, and leveraged it to identify drug candidates for expanded use in adenocarcinomas. The FDA-approved drugs identified through this pipeline serve as candidates to repurpose as pan-adenocarcinoma anti-cancer therapeutics, reducing both time and cost for drug development. ConclusionOur research provided insights into the common molecular mechanisms across multiple adenocarcinomas and unveiled potential drug candidates for future therapeutic testing.