Abstract 1079: L2S2: Chemical perturbation and CRISPR KO LINCS L1000 signature search engine

The Library of Integrated Network-Based Cellular Signatures (LINCS) Common Fund program was established to construct a reference database of human cancer cell lines responses to diverse multi-omics and phenotypic perturbations. As part of the LINCS initiative, 248 cell lines were profiled with the L1000 transcriptomics assay to measure the response to 33,621 small molecules and 7,508 single gene CRISPR knockouts (KOs). From this massive dataset, we computed sets of up- and down-regulated genes. These gene sets are served for search by the LINCS L1000 Signature Search (L2S2) platform. L2S2 provides instant results when searching across over 1.678 million chemical perturbations and CRISPR KO signatures. The platform includes filters for FDA-approved drugs and signature directionality. With the L2S2 search engine, users can identify small molecules and single gene CRISPR KOs that produce gene expression profiles similar or opposite to their submitted gene sets. Significant CRISPR KO signatures can reveal potential driver genes and drug targets. Similarly, approved drugs and preclinical small molecule signatures that might reverse or mimic a desired expression pattern can provide hypotheses for preclinical experimental validation studies. L2S2 also includes a consensus search feature which ranks specific perturbations across cellular contexts, time points, and concentrations. L2S2 was systematically applied to the CPTAC3 cohort to prioritize potential targets, approved drugs, and preclinical compounds for all previously identified multi-omic cancer cohort subtypes. Overall, L2S2 provides cancer researchers with a powerful tool to further understand and personalize treatments for cancer subtypes. L2S2 is available from: https://l2s2.maayanlab.cloud. Citation Format: Giacomo B. Marino, John E. Evangelista, Daniel J. Clarke, Avi Ma'ayan. L2S2: Chemical perturbation and CRISPR KO LINCS L1000 signature search engine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1079.