The Deep Core: Mapping the 0.91% Regulatory Backbone of the Human Proteome and Its Role in Cancer Drug Resistance

The Deep Core: Mapping the 0.91% Regulatory Backbone of the Human Proteome and Its Role in Cancer Drug Resistance | 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 Article The Deep Core: Mapping the 0.91% Regulatory Backbone of the Human Proteome and Its Role in Cancer Drug Resistance Andres Pirolo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8167100/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 We present a computational method to identify the minimal regulatory backbone of the human proteome using multi-distance dominating set analysis. Applying our DeepDS algorithm to the human protein-protein interaction network, we identified a Deep Core of 144 proteins (0.91%) that achieve complete topological control of the network within 3 interaction steps. Comparative analysis across 7 species reveals that topological efficiency is an evolution- ary trait: humans (0.91%) are significantly more centralized than mice (3.29%), revealing a ”Modularity Gap” of 3.65×. Only 12 proteins are topologically conserved between mam- mals (”The 12 Immortals”), representing the irreducible machinery of life including EGFR, PLK1, and CASP3. We demonstrate that cancer preferentially hijacks this Deep Core. Intersection with clinical data reveals that 13.2% of the core consists of cancer drivers, including the ”Sinister Six” (TP53, EGFR, PLK1, SRC, SP1, CEP290). Finally, we validate a network-based mechanism of drug resistance. Statistical analysis of pharmacogenomic data (N = 321) reveals a strong correlation (r = 0.764, p < 0.0001) between high GNAL expression and Erlotinib resistance. Biological sciences/Cancer/Cancer models Health sciences/Medical research/Biomarkers Deep Core Network Medicine GNAL Resistance Evolutionary Rewiring Drug Resistance Systems Pharmacology Cancer Biology Full Text Additional Declarations There is NO conflict of interest to disclose. 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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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8167100","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":585123859,"identity":"5c091315-4478-46c5-9ae3-5bdb83e01b43","order_by":0,"name":"Andres Pirolo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIie3RMQuCQBTA8Xe4Cq0GcfcVnrT6YXTJJaHRUTiwsdXwU/QNCqFJmgVvSAJngwbHrrKh6dkWdP/tjvfjeByAyfSTsQRgBRyc52k/liDMvyGPEIJkNJnkMu069MJNLs/sFit9QzBHHeQ2w0WUqSNas7IF5+QTz1SBtGwsoqRagjVNC4CSEGIgoXgTQREciI+asKsmSBFX78L0Lu5O71JA2douRXi9vkAXe4LXsmn6WHFOkeEHXxU2gE2BT8J6et5kMpn+sDuNgUaed4kEfAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0004-3899-1222","institution":"Ministerio de Educacion y Ciencia","correspondingAuthor":true,"prefix":"","firstName":"Andres","middleName":"","lastName":"Pirolo","suffix":""}],"badges":[],"createdAt":"2025-11-20 17:55:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8167100/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8167100/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101881160,"identity":"22d52eb1-554a-4822-ba56-2383ad6a37f7","added_by":"auto","created_at":"2026-02-04 15:10:19","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1220926,"visible":true,"origin":"","legend":"Article File","description":"","filename":"PiroloDeepCoreCancerResistanceCOMPLETE1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8167100/v1_covered_1a97bf96-79db-41a0-ad55-0b886062d46f.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"The Deep Core: Mapping the 0.91% Regulatory\nBackbone of the Human Proteome and Its Role in\nCancer Drug Resistance","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Deep Core, Network Medicine, GNAL Resistance, Evolutionary Rewiring, Drug Resistance, Systems Pharmacology, Cancer Biology","lastPublishedDoi":"10.21203/rs.3.rs-8167100/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8167100/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"We present a computational method to identify the minimal regulatory backbone of\r\nthe human proteome using multi-distance dominating set analysis. Applying our DeepDS\r\nalgorithm to the human protein-protein interaction network, we identified a Deep Core of\r\n144 proteins (0.91%) that achieve complete topological control of the network within 3\r\ninteraction steps.\r\nComparative analysis across 7 species reveals that topological efficiency is an evolution-\r\nary trait: humans (0.91%) are significantly more centralized than mice (3.29%), revealing a\r\n”Modularity Gap” of 3.65×. Only 12 proteins are topologically conserved between mam-\r\nmals (”The 12 Immortals”), representing the irreducible machinery of life including EGFR,\r\nPLK1, and CASP3.\r\nWe demonstrate that cancer preferentially hijacks this Deep Core. Intersection with\r\nclinical data reveals that 13.2% of the core consists of cancer drivers, including the ”Sinister\r\nSix” (TP53, EGFR, PLK1, SRC, SP1, CEP290).\r\nFinally, we validate a network-based mechanism of drug resistance. Statistical analysis\r\nof pharmacogenomic data (N = 321) reveals a strong correlation (r = 0.764, p \u003c 0.0001)\r\nbetween high GNAL expression and Erlotinib resistance.","manuscriptTitle":"The Deep Core: Mapping the 0.91% Regulatory\nBackbone of the Human Proteome and Its Role in\nCancer Drug Resistance","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-04 03:31:45","doi":"10.21203/rs.3.rs-8167100/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7ed727bf-6cb6-4906-b82a-ae86a741369f","owner":[],"postedDate":"February 4th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":62248283,"name":"Biological sciences/Cancer/Cancer models"},{"id":62248284,"name":"Health sciences/Medical research/Biomarkers"}],"tags":[],"updatedAt":"2026-02-04T03:31:45+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-04 03:31:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8167100","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8167100","identity":"rs-8167100","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}