{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T12:44:13Z","timestamp":1779108253517,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009515","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T00:00:00Z","timestamp":1637280000000}}],"reference-count":62,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T00:00:00Z","timestamp":1635984000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017268","name":"Berlin Institute of Health","doi-asserted-by":"crossref","award":["CRG1"],"award-info":[{"award-number":["CRG1"]}],"id":[{"id":"10.13039\/501100017268","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["MSTARS"],"award-info":[{"award-number":["MSTARS"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and mathematical modelling, we determined potential resistance mechanisms. We found that negative feedbacks within MAPK signalling and via the IGF receptor mediate re-activation of MAPK signalling upon treatment in resistant cell lines. By using cell-line specific models, we predict that combinations of MEK inhibitors with RAF or IGFR inhibitors can overcome resistance, and tested these predictions experimentally. In addition, phospho-proteomic profiling confirmed the cell-specific feedback effects and synergy of MEK and IGFR targeted treatment. Our study shows that a quantitative understanding of signalling and feedback mechanisms facilitated by models can help to develop and optimise therapeutic strategies. Our findings should be considered for the planning of future clinical trials introducing MEKi in the treatment of neuroblastoma.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009515","type":"journal-article","created":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T13:48:07Z","timestamp":1636033687000},"page":"e1009515","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1663-2075","authenticated-orcid":true,"given":"Mathurin","family":"Dorel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0242-1506","authenticated-orcid":true,"given":"Bertram","family":"Klinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6011-9386","authenticated-orcid":true,"given":"Tommaso","family":"Mari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1471-1295","authenticated-orcid":true,"given":"Joern","family":"Toedling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4369-0254","authenticated-orcid":true,"given":"Eric","family":"Blanc","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8632-656X","authenticated-orcid":true,"given":"Clemens","family":"Messerschmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Nadler-Holly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7074-4054","authenticated-orcid":true,"given":"Matthias","family":"Ziehm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6588-8547","authenticated-orcid":true,"given":"Anja","family":"Sieber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4784-6516","authenticated-orcid":true,"given":"Falk","family":"Hertwig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dieter","family":"Beule","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelika","family":"Eggert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0671-1201","authenticated-orcid":true,"given":"Johannes H.","family":"Schulte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2454-8751","authenticated-orcid":true,"given":"Matthias","family":"Selbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0171-7447","authenticated-orcid":true,"given":"Nils","family":"Bl\u00fcthgen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,11,4]]},"reference":[{"issue":"8","key":"pcbi.1009515.ref001","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1200\/JCO.2003.05.191","article-title":"Disseminated neuroblastoma in children older than one year at diagnosis: Comparable results with three consecutive high-dose protocols adopted by the Italian Co-Operatiye Group for Neuroblastoma","volume":"21","author":"B De Bernardi","year":"2003","journal-title":"Journal of Clinical Oncology"},{"issue":"9579","key":"pcbi.1009515.ref002","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1016\/S0140-6736(07)60983-0","article-title":"Neuroblastoma","volume":"369","author":"JM Maris","year":"2007","journal-title":"Lancet"},{"issue":"1","key":"pcbi.1009515.ref003","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.canlet.2011.02.016","article-title":"Identification of therapy-sensitive and therapy-resistant neuroblastoma subtypes in stages III, IVs and IV","volume":"306","author":"Y Kyo","year":"2011","journal-title":"Cancer Letters"},{"issue":"7575","key":"pcbi.1009515.ref004","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1038\/nature14980","article-title":"Telomerase activation by genomic rearrangements in high-risk neuroblastoma","volume":"526","author":"M Peifer","year":"2015","journal-title":"Nature"},{"issue":"21","key":"pcbi.1009515.ref005","doi-asserted-by":"crossref","first-page":"5814","DOI":"10.1158\/1078-0432.CCR-13-0680","article-title":"New strategies in neuroblastoma: Therapeutic targeting of MYCN and ALK","volume":"19","author":"G Barone","year":"2013","journal-title":"Clinical cancer research: an official journal of the American Association for Cancer Research"},{"issue":"6419","key":"pcbi.1009515.ref006","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1126\/science.aat6768","article-title":"A mechanistic classification of clinical phenotypes in neuroblastoma","volume":"362","author":"S Ackermann","year":"2018","journal-title":"Science"},{"issue":"8","key":"pcbi.1009515.ref007","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/ng.3333","article-title":"Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations","volume":"47","author":"TF Eleveld","year":"2015","journal-title":"Nature genetics"},{"issue":"5","key":"pcbi.1009515.ref008","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.ccell.2014.09.019","article-title":"ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma","volume":"26","author":"SC Bresler","year":"2014","journal-title":"Cancer Cell"},{"issue":"suppl3","key":"pcbi.1009515.ref009","doi-asserted-by":"crossref","first-page":"iii4","DOI":"10.1093\/annonc\/mdw301","article-title":"The role of the ALK receptor in cancer biology","volume":"27","author":"B Hallberg","year":"2016","journal-title":"Annals of Oncology"},{"issue":"3","key":"pcbi.1009515.ref010","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/ng.2529","article-title":"The genetic landscape of high-risk neuroblastoma","volume":"45","author":"TJ Pugh","year":"2013","journal-title":"Nature Genetics"},{"key":"pcbi.1009515.ref011","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.phrs.2018.02.023","article-title":"Molecular mechanisms and therapeutic targets in neuroblastoma","volume":"131","author":"JI Johnsen","year":"2018","journal-title":"Pharmacological Research"},{"issue":"6","key":"pcbi.1009515.ref012","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.ccr.2012.10.023","article-title":"JAK2\/STAT5 Inhibition Circumvents Resistance to PI3K\/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer","volume":"22","author":"A Britschgi","year":"2012","journal-title":"Cancer Cell"},{"issue":"1","key":"pcbi.1009515.ref013","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/msb.2013.29","article-title":"Network quantification of EGFR signaling unveils potential for targeted combination therapy","volume":"9","author":"B Klinger","year":"2013","journal-title":"Molecular Systems Biology"},{"issue":"7387","key":"pcbi.1009515.ref014","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nature10868","article-title":"Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR","volume":"483","author":"A Prahallad","year":"2012","journal-title":"Nature"},{"issue":"15","key":"pcbi.1009515.ref015","doi-asserted-by":"crossref","first-page":"6145","DOI":"10.1158\/0008-5472.CAN-08-1430","article-title":"BRAF V600E disrupts AZD6244-induced abrogation of negative feedback pathways between extracellular signal-regulated kinase and Raf proteins","volume":"68","author":"BB Friday","year":"2008","journal-title":"Cancer Research"},{"issue":"1","key":"pcbi.1009515.ref016","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/msb.2011.27","article-title":"Strong negative feedback from Erk to Raf confers robustness to MAPK signalling","volume":"7","author":"R Fritsche-Guenther","year":"2011","journal-title":"Molecular Systems Biology"},{"issue":"153","key":"pcbi.1009515.ref017","doi-asserted-by":"crossref","first-page":"ra90","DOI":"10.1126\/scisignal.2001212","article-title":"The mammalian MAPK\/ERK pathway exhibits properties of a negative feedback amplifier","volume":"3","author":"OE Sturm","year":"2010","journal-title":"Science Signaling"},{"issue":"4","key":"pcbi.1009515.ref018","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1042\/BST20140130","article-title":"Consequences of feedback in signal transduction for targeted therapies","volume":"42","author":"B Klinger","year":"2014","journal-title":"Biochemical Society Transactions"},{"key":"pcbi.1009515.ref019","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/s12885-016-2199-z","article-title":"Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression","volume":"16","author":"SE Woodfield","year":"2016","journal-title":"BMC cancer"},{"issue":"1","key":"pcbi.1009515.ref020","doi-asserted-by":"crossref","first-page":"e0170851","DOI":"10.1371\/journal.pone.0147682","article-title":"Targeting the mTOR complex by everolimus in NRAS mutant neuroblastoma","volume":"11","author":"MK Kiessling","year":"2016","journal-title":"PLoS ONE"},{"issue":"23","key":"pcbi.1009515.ref021","doi-asserted-by":"crossref","first-page":"4079","DOI":"10.1093\/bioinformatics\/bty473","article-title":"Modelling signalling networks from perturbation data","volume":"34","author":"M Dorel","year":"2018","journal-title":"Bioinformatics"},{"issue":"5","key":"pcbi.1009515.ref022","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/j.cellsig.2011.12.021","article-title":"Dual specificity phosphatases 10 and 16 are positive regulators of EGF-stimulated ERK activity: Indirect regulation of ERK signals by JNK\/p38 selective MAPK phosphatases","volume":"24","author":"AR Finch","year":"2012","journal-title":"Cellular Signalling"},{"issue":"9","key":"pcbi.1009515.ref023","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1091\/mbc.E18-10-0676","article-title":"Isoform-specific Ras signaling is growth factor dependent","volume":"30","author":"FE Hood","year":"2019","journal-title":"Molecular Biology of the Cell"},{"issue":"2","key":"pcbi.1009515.ref024","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.molcel.2012.05.007","article-title":"Cooperative Activation of PI3K by Ras and Rho Family Small GTPases","volume":"47","author":"HW Yang","year":"2012","journal-title":"Molecular Cell"},{"issue":"3","key":"pcbi.1009515.ref025","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1158\/2159-8290.CD-11-0341","article-title":"EGFR-mediated reactivation of MAPK signaling contributes to insensitivity of BRAF-mutant colorectal cancers to RAF inhibition with vemurafenib","volume":"2","author":"RB Corcoran","year":"2012","journal-title":"Cancer Discovery"},{"issue":"11","key":"pcbi.1009515.ref026","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1158\/1535-7163.MCT-14-0330","article-title":"Suppression of feedback loops mediated by pi3k\/mtor induces multiple overactivation of compensatory pathways: An unintended consequence leading to drug resistance","volume":"13","author":"E Rozengurt","year":"2014","journal-title":"Molecular Cancer Therapeutics"},{"key":"pcbi.1009515.ref027","doi-asserted-by":"crossref","unstructured":"Lake D, Corr\u00eaa SAL, M\u00fcller J. Negative feedback regulation of the ERK1\/2 MAPK pathway; 2016. Available from: http:\/\/link.springer.com\/10.1007\/s00018-016-2297-8.","DOI":"10.1007\/s00018-016-2297-8"},{"issue":"7","key":"pcbi.1009515.ref028","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1038\/s41596-018-0006-9","article-title":"Reproducible workflow for multiplexed deep-scale proteome and phosphoproteome analysis of tumor tissues by liquid chromatography-mass spectrometry","volume":"13","author":"P Mertins","year":"2018","journal-title":"Nature Protocols"},{"issue":"4","key":"pcbi.1009515.ref029","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/s41592-020-0781-4","article-title":"TMTpro reagents: a set of isobaric labeling mass tags enables simultaneous proteome-wide measurements across 16 samples","volume":"17","author":"J Li","year":"2020","journal-title":"Nature Methods"},{"issue":"12","key":"pcbi.1009515.ref030","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1038\/sj.emboj.7601166","article-title":"The mTOR\/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity","volume":"25","author":"D Shahbazian","year":"2006","journal-title":"The EMBO Journal"},{"key":"pcbi.1009515.ref031","doi-asserted-by":"crossref","unstructured":"Casado P, Rodriguez-Prados JC, Cosulich SC, Guichard S, Vanhaesebroeck B, Joel S, et al. Kinase-substrate enrichment analysis provides insights into the heterogeneity of signaling pathway activation in leukemia cells; 2013. Available from: http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23532336.","DOI":"10.1126\/scisignal.2003573"},{"issue":"3","key":"pcbi.1009515.ref032","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.devcel.2005.07.014","article-title":"The Cdk1 complex plays a prime role in regulating N-myc phosphorylation and turnover in neural precursors","volume":"9","author":"SK Sjostrom","year":"2005","journal-title":"Developmental Cell"},{"issue":"3","key":"pcbi.1009515.ref033","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.ccr.2014.07.015","article-title":"Drugging MYCN through an Allosteric Transition in Aurora Kinase A","volume":"26","author":"WC Gustafson","year":"2014","journal-title":"Cancer Cell"},{"key":"pcbi.1009515.ref034","doi-asserted-by":"crossref","unstructured":"Tang J, Wennerberg K, Aittokallio T. What is synergy? The Saariselk\u00e4 agreement revisited; 2015. Available from: http:\/\/journal.frontiersin.org\/article\/10.3389\/fphar.2015.00181.","DOI":"10.3389\/fphar.2015.00181"},{"issue":"18","key":"pcbi.1009515.ref035","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1093\/bioinformatics\/bts459","article-title":"Network inference using steady-state data and goldbeter-koshland kinetics","volume":"28","author":"CJ Oates","year":"2012","journal-title":"Bioinformatics"},{"issue":"1","key":"pcbi.1009515.ref036","first-page":"1","article-title":"Large-scale models of signal propagation in human cells derived from discovery phosphoproteomic data","volume":"6","author":"CDA Terfve","year":"2015","journal-title":"Nature Communications"},{"key":"pcbi.1009515.ref037","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/1752-0509-7-57","article-title":"Integrating Bayesian variable selection with Modular Response Analysis to infer biochemical network topology","volume":"7","author":"T Santra","year":"2013","journal-title":"BMC systems biology"},{"issue":"4","key":"pcbi.1009515.ref038","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1042\/EBC20180019","article-title":"Reconstructing phosphorylation signalling networks from quantitative phosphoproteomic data","volume":"62","author":"BM Invergo","year":"2018","journal-title":"Essays in Biochemistry"},{"key":"pcbi.1009515.ref039","doi-asserted-by":"crossref","first-page":"862","DOI":"10.3389\/fphys.2020.00862","article-title":"Strategies to Enhance Logic Modeling-Based Cell Line-Specific Drug Synergy Prediction","volume":"11","author":"B Niederdorfer","year":"2020","journal-title":"Frontiers in Physiology"},{"issue":"18","key":"pcbi.1009515.ref040","doi-asserted-by":"crossref","first-page":"5046","DOI":"10.1128\/MCB.00315-09","article-title":"The Absence of Caveolin-1 Increases Proliferation and Anchorage- Independent Growth by a Rac-Dependent, Erk-Independent Mechanism","volume":"29","author":"A Cerezo","year":"2009","journal-title":"Molecular and Cellular Biology"},{"issue":"4","key":"pcbi.1009515.ref041","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1002\/jcb.23458","article-title":"M-Ras induces Ral and JNK activation to regulate MEK\/ERK-independent gene expression in MCF-7 breast cancer cells","volume":"113","author":"AF Castro","year":"2012","journal-title":"Journal of Cellular Biochemistry"},{"key":"pcbi.1009515.ref042","doi-asserted-by":"crossref","first-page":"e04640","DOI":"10.7554\/eLife.04640","article-title":"Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells","volume":"4","author":"A Korkut","year":"2015","journal-title":"eLife"},{"issue":"3","key":"pcbi.1009515.ref043","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1073\/pnas.90.3.1112","article-title":"Redundant cyclin overexpression and gene amplification in breast cancer cells","volume":"90","author":"K Keyomarsi","year":"1993","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"1","key":"pcbi.1009515.ref044","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1186\/1471-2407-14-951","article-title":"High nuclear\/cytoplasmic ratio of cdk1 expression predicts poor prognosis in colorectal cancer patients","volume":"14","author":"WW Sung","year":"2014","journal-title":"BMC Cancer"},{"issue":"1","key":"pcbi.1009515.ref045","doi-asserted-by":"crossref","first-page":"2919","DOI":"10.1038\/s41467-019-10954-y","article-title":"Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium","volume":"10","author":"R Brandt","year":"2019","journal-title":"Nature Communications"},{"issue":"1","key":"pcbi.1009515.ref046","doi-asserted-by":"crossref","first-page":"e9042","DOI":"10.15252\/msb.20199042","article-title":"Personalized signaling models for personalized treatments","volume":"16","author":"J Saez-Rodriguez","year":"2020","journal-title":"Molecular Systems Biology"},{"issue":"5","key":"pcbi.1009515.ref047","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1002\/ijc.32639","article-title":"CLASTR: The Cellosaurus STR similarity search tool\u2014A precious help for cell line authentication","volume":"146","author":"T Robin","year":"2019","journal-title":"International Journal of Cancer"},{"key":"pcbi.1009515.ref048","unstructured":"Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXivorg. 2013;."},{"issue":"17","key":"pcbi.1009515.ref049","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1093\/bioinformatics\/btu314","article-title":"SAMBLASTER: fast duplicate marking and structural variant read extraction","volume":"30","author":"GG Faust","year":"2014","journal-title":"Bioinformatics"},{"issue":"4","key":"pcbi.1009515.ref050","doi-asserted-by":"crossref","first-page":"e1004873","DOI":"10.1371\/journal.pcbi.1004873","article-title":"CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing","volume":"12","author":"E Talevich","year":"2016","journal-title":"PLOS Computational Biology"},{"issue":"8","key":"pcbi.1009515.ref051","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/s41592-018-0051-x","article-title":"Strelka2: fast and accurate calling of germline and somatic variants","volume":"15","author":"S Kim","year":"2018","journal-title":"Nature Methods"},{"key":"pcbi.1009515.ref052","unstructured":"Auton A, Abecasis GR, Altshuler DM, Durbin RM, Bentley DR, Chakravarti A, et al. A global reference for human genetic variation; 2015. Available from: http:\/\/www.nature.com\/articles\/nature15393."},{"issue":"7431","key":"pcbi.1009515.ref053","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nature11690","article-title":"Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants","volume":"493","author":"W Fu","year":"2013","journal-title":"Nature"},{"issue":"1","key":"pcbi.1009515.ref054","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"A Dobin","year":"2013","journal-title":"Bioinformatics"},{"issue":"7","key":"pcbi.1009515.ref055","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"FeatureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Y Liao","year":"2014","journal-title":"Bioinformatics"},{"issue":"15","key":"pcbi.1009515.ref056","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1093\/bioinformatics\/btx162","article-title":"SynergyFinder: A web application for analyzing drug combination dose-response matrix data","volume":"33","author":"A Ianevski","year":"2017","journal-title":"Bioinformatics"},{"issue":"9 Supplement","key":"pcbi.1009515.ref057","first-page":"DDT01","article-title":"MK-2206: A potent oral allosteric AKT inhibitor","volume":"69","author":"L Yan","year":"2009","journal-title":"Cancer Research"},{"issue":"1","key":"pcbi.1009515.ref058","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/s41596-018-0082-x","article-title":"Single-pot, solid-phase-enhanced sample preparation for proteomics experiments","volume":"14","author":"CS Hughes","year":"2019","journal-title":"Nature Protocols"},{"issue":"12","key":"pcbi.1009515.ref059","doi-asserted-by":"crossref","first-page":"6176","DOI":"10.1021\/pr500893m","article-title":"Off-line high-pH reversed-phase fractionation for in-depth phosphoproteomics","volume":"13","author":"TS Batth","year":"2014","journal-title":"Journal of Proteome Research"},{"issue":"12","key":"pcbi.1009515.ref060","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1038\/nprot.2016.136","article-title":"The MaxQuant computational platform for mass spectrometry-based shotgun proteomics","volume":"11","author":"S Tyanova","year":"2016","journal-title":"Nature Protocols"},{"issue":"7","key":"pcbi.1009515.ref061","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"ME Ritchie","year":"2015","journal-title":"Nucleic Acids Research"},{"issue":"D1","key":"pcbi.1009515.ref062","doi-asserted-by":"crossref","first-page":"D512","DOI":"10.1093\/nar\/gku1267","article-title":"PhosphoSitePlus, 2014: Mutations, PTMs and recalibrations","volume":"43","author":"PV Hornbeck","year":"2015","journal-title":"Nucleic Acids Research"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1009515","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T00:00:00Z","timestamp":1637280000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009515","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T13:44:17Z","timestamp":1637329457000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009515"}},"subtitle":[],"editor":[{"given":"Inna","family":"Lavrik","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,11,4]]},"references-count":62,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11,4]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009515","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.06.14.448322","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,4]]}}}