Confounder-adjusted analysis of statin selectivity across cancer cell lines identifies a colorectal-enriched SLC45A4 signal

Confounder-adjusted analysis of statin selectivity across cancer cell lines identifies a colorectal-enriched SLC45A4 signal | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Confounder-adjusted analysis of statin selectivity across cancer cell lines identifies a colorectal-enriched SLC45A4 signal Takayuki Sakuma This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9218378/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Large-scale pharmacogenomic screens enable systematic searches for genetic determinants of drug sensitivity, but cross–cell-line analyses are confounded by lineage structure and drugfree proliferation rates. We integrate DepMap genome-scale CRISPR dependency profiles with PRISM viability responses and estimate covariate-adjusted associations between gene dependency and a statin selectivity phenotype using cross-fitted double machine learning (DML). The analysis recovers mevalonate-pathway regulators (MVK, UBIAD1) and identifies SLC45A4 as a colorectal-enriched candidate association. To assess robustness, we validate findings in independent AUC datasets, conduct leave-one-drug-out sensitivity analyses, and benchmark against empirical-null drug-bundle and gene-level negative controls. In colorectal lines, the SLC45A4 signal aligns with sterol-biosynthesis-related co-dependency and colorectal-specific shifts in polyunsaturated cholesteryl esters and putrescine in CCLE metabolomics. As positive controls, expected EGFR- and BRAF-matched drug responses were reproduced in independent datasets. These results reduce concern that the SLC45A4 association is explained solely by cross-dataset integration bias and support further experimental testing. Cancer Biology Oncology Bioinformatics Computational Biology Clinical Pharmacology Drug Discovery, Design, & Development DepMap PRISM statins mevalonate pathway causal inference double machine learning pharmacogenomics Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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