2024
Systems modeling of oncogenic G-protein and GPCR signaling reveals unexpected differences in downstream pathway activation
Trogdon M, Abbott K, Arang N, Lande K, Kaur N, Tong M, Bakhoum M, Gutkind J, Stites E. Systems modeling of oncogenic G-protein and GPCR signaling reveals unexpected differences in downstream pathway activation. Npj Systems Biology And Applications 2024, 10: 75. PMID: 39013872, PMCID: PMC11252164, DOI: 10.1038/s41540-024-00400-1.Peer-Reviewed Original ResearchConceptsSignaling networksMathematical models of biochemical reaction networksModels of biochemical reaction networksG-proteinCell signaling networksDisease-causing mutationsComputational systems biologyBiochemical reaction networksDownstream pathway activationSignaling phenotypeSystems biologyBioinformatics analysisGPCR signalingMutationsCo-occurring mutationsOncogenic mutationsPathway activationDiscovery toolPathwayReaction networkSignalCYSLTR2 mutationsDiscoveryPhenotypeMutually-exclusiveThe Abundance of KRAS and RAS Gene Mutations in Cancer
Stites E. The Abundance of KRAS and RAS Gene Mutations in Cancer. Methods In Molecular Biology 2024, 2797: 13-22. PMID: 38570449, DOI: 10.1007/978-1-0716-3822-4_2.Peer-Reviewed Original Research
2021
Identification of RAS mutant biomarkers for EGFR inhibitor sensitivity using a systems biochemical approach
McFall T, Stites E. Identification of RAS mutant biomarkers for EGFR inhibitor sensitivity using a systems biochemical approach. Cell Reports 2021, 37: 110096. PMID: 34910921, PMCID: PMC8867612, DOI: 10.1016/j.celrep.2021.110096.Peer-Reviewed Original ResearchConceptsSensitivity to EGFR inhibitionSubsets of mutationsRAS mutationsKRAS G13DCancer cell biologyEGFR inhibitionEpidermal growth factor receptor (EGFR)-targeted therapyTumor suppressor neurofibrominGene-basedBiophysical biomarkersInhibitor sensitivityCell biologyMutationsPersonalized medicineBiomarker strategiesKRAS mutantRasCancer treatmentKRASNF1BiomarkersBiophysical characteristicsG13DMutantsInhibitionCancer gene mutation frequencies for the U.S. population
Mendiratta G, Ke E, Aziz M, Liarakos D, Tong M, Stites E. Cancer gene mutation frequencies for the U.S. population. Nature Communications 2021, 12: 5961. PMID: 34645806, PMCID: PMC8514428, DOI: 10.1038/s41467-021-26213-y.Peer-Reviewed Original ResearchMeSH KeywordsComputational BiologyDNA-Binding ProteinsEpigenesis, GeneticGene Expression Regulation, NeoplasticGenetics, PopulationHumansIncidenceMutation RateNeoplasm ProteinsNeoplasmsPhosphatidylinositol 3-KinasesProto-Oncogene Proteins B-rafProto-Oncogene Proteins p21(ras)Terminology as TopicTranscription FactorsTumor Suppressor Protein p53United StatesConceptsMutated driver genesMutant formsCancer driversCancer geneticsCancer casesDriver genesGene mutation frequencyMutated genesU.S. populationEpigenetic dysregulationMutation frequencyDevelopment of cancerGenesPublic healthEpidemiological dataCancer typesTargetable vulnerabilitiesCancerKMT2CPopulationMutationsHealthGeneticsKMT2DMathematical Modeling to Study KRAS Mutant-Specific Responses to Pathway Inhibition
Stites E. Mathematical Modeling to Study KRAS Mutant-Specific Responses to Pathway Inhibition. Methods In Molecular Biology 2021, 2262: 311-321. PMID: 33977486, PMCID: PMC8639139, DOI: 10.1007/978-1-0716-1190-6_19.Peer-Reviewed Original ResearchConceptsRegulates Ras signalingMutant Ras proteinsKRAS G13D mutationRas proteinsRAS communityRas mutantsRas signalingRas pathwayBiochemical reactionsWild-typeRasMutationsPathway inhibitionG13D mutationDose-response experimentsMutantsKnowledge of reaction mechanismsInhibitionEGFR inhibitionKRAS mutationsProteinKRASKRAS‐Mutated, Estrogen Receptor‐Positive Low‐Grade Serous Ovarian Cancer: Unraveling an Exceptional Response Mystery
Kato S, McFall T, Takahashi K, Bamel K, Ikeda S, Eskander R, Plaxe S, Parker B, Stites E, Kurzrock R. KRAS‐Mutated, Estrogen Receptor‐Positive Low‐Grade Serous Ovarian Cancer: Unraveling an Exceptional Response Mystery. The Oncologist 2021, 26: e530-e536. PMID: 33528846, PMCID: PMC8018312, DOI: 10.1002/onco.13702.Peer-Reviewed Original ResearchConceptsMEK inhibitorsMechanism of actionOvarian cancerAromatase inhibitorsEstrogen modulationKRAS-mutantLow-grade serous ovarian cancerCombination of trametinibEstrogen receptor-positiveSerous ovarian cancerPrecision medicine strategiesPI3K inhibitorsReceptor-positiveCombination therapyEstrogen depletionTamoxifenTrametinibAgonist effectsIn vitro investigationLetrozoleEstrogenIn vitro experimentsMedicine strategiesMEKExceptional response
2020
Discernment between candidate mechanisms for KRAS G13D colorectal cancer sensitivity to EGFR inhibitors
McFall T, Schomburg N, Rossman K, Stites E. Discernment between candidate mechanisms for KRAS G13D colorectal cancer sensitivity to EGFR inhibitors. Cell Communication And Signaling 2020, 18: 179. PMID: 33153459, PMCID: PMC7643456, DOI: 10.1186/s12964-020-00645-3.Peer-Reviewed Original ResearchConceptsKRAS mutationsKRAS G13DEGFR inhibitorsColorectal cancerSensitivity to EGFR inhibitorsRas-GTP levelsSensitivity to cetuximabClinical trial evidenceWild-type RasGTPase activityKRAS G13D mutationBind NF1Tumor suppressor NF1EGFR inhibitionG13D mutationKRASCetuximabBiophysical studiesTrial evidenceG13DWild-typeNF1MutationsCellular modelEGFRReal-world data from a molecular tumor board demonstrates improved outcomes with a precision N-of-One strategy
Kato S, Kim K, Lim H, Boichard A, Nikanjam M, Weihe E, Kuo D, Eskander R, Goodman A, Galanina N, Fanta P, Schwab R, Shatsky R, Plaxe S, Sharabi A, Stites E, Adashek J, Okamura R, Lee S, Lippman S, Sicklick J, Kurzrock R. Real-world data from a molecular tumor board demonstrates improved outcomes with a precision N-of-One strategy. Nature Communications 2020, 11: 4965. PMID: 33009371, PMCID: PMC7532150, DOI: 10.1038/s41467-020-18613-3.Peer-Reviewed Original ResearchConceptsMolecular tumor boardOverall survivalTumor boardNext-generation sequencingReviewed patient characteristicsResistant to monotherapyProgression-freeOncological outcomesRemission rateChoice regimenGenomic alterationsPatient characteristicsRecommended drugsMolecular findingsPatientsTherapyMaster protocolCancer targetPhysician-directedPFSPrecision strategySurvivalDrugMedication accessOutcomesThe Interpretation of SARS-CoV-2 Diagnostic Tests
Stites EC, Wilen CB. The Interpretation of SARS-CoV-2 Diagnostic Tests. Med 2020, 1: 78-89. PMID: 32864639, PMCID: PMC7441939, DOI: 10.1016/j.medj.2020.08.001.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 diagnostic testsCOVID-19SARS-CoV-2Diagnostic laboratory testingAsymptomatic individualsOngoing COVID-19 pandemicGeneral populationTesting utilizationMedical careDiagnostic testsMedical communityInformed decision makingCOVID-19 pandemicImmunity passportsTest interpretationDiseaseLaboratory testing
2019
A systems mechanism for KRAS mutant allele–specific responses to targeted therapy
McFall T, Diedrich J, Mengistu M, Littlechild S, Paskvan K, Sisk-Hackworth L, Moresco J, Shaw A, Stites E. A systems mechanism for KRAS mutant allele–specific responses to targeted therapy. Science Signaling 2019, 12 PMID: 31551296, PMCID: PMC6864030, DOI: 10.1126/scisignal.aaw8288.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorWild-type Ras activationColorectal cancerSensitivity to EGFR inhibitionEpidermal growth factor receptor inhibitionKRAS mutantEGFR-independent mannerAllele-specific responsesRas activationGrowth factor receptorTumor suppressor neurofibrominPatient tumorsAntibody cetuximabTargeted therapyMechanisms of EGFR signalingCRC patientsEGFR inhibitionCancer treatment decisionsRAS mutationsFactor receptorKRASTherapeutic strategiesTreatment decisionsEGFR signalingPatientsModeling cell line-specific recruitment of signaling proteins to the insulin-like growth factor 1 receptor
Erickson KE, Rukhlenko OS, Shahinuzzaman M, Slavkova KP, Lin YT, Suderman R, Stites EC, Anghel M, Posner RG, Barua D, Kholodenko BN, Hlavacek WS. Modeling cell line-specific recruitment of signaling proteins to the insulin-like growth factor 1 receptor. PLOS Computational Biology 2019, 15: e1006706. PMID: 30653502, PMCID: PMC6353226, DOI: 10.1371/journal.pcbi.1006706.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesSrc homology 2Autophosphorylation sitesInsulin-like growth factor 1 receptorGrowth factor 1 receptorFactor 1 receptorPTB domain-containing proteinsCopy numberDomain-containing proteinsPhosphotyrosine-binding (PTB) domainProtein copy numbersMultiple autophosphorylation sitesProtein abundance profilesMultiple signaling proteinsShort linear motifsOutcome of competitionCell line-specific modelsHomology 2Cytoplasmic domainSignaling proteinsLinear motifsTyrosine kinaseEffects of competitionRule-based modeling approachRelative abundance
2018
Proceedings of the fifth international RASopathies symposium: When development and cancer intersect
Rauen K, Schoyer L, Schill L, Stronach B, Albeck J, Andresen B, Cavé H, Ellis M, Fruchtman S, Gelb B, Gibson C, Gripp K, Hefner E, Huang W, Itkin M, Kerr B, Linardic C, McMahon M, Oberlander B, Perlstein E, Ratner N, Rogers L, Schenck A, Shankar S, Shvartsman S, Stevenson D, Stites E, Stork P, Sun C, Therrien M, Ullian E, Widemann B, Yeh E, Zampino G, Zenker M, Timmer W, McCormick F. Proceedings of the fifth international RASopathies symposium: When development and cancer intersect. American Journal Of Medical Genetics Part A 2018, 176: 2924-2929. PMID: 30302932, PMCID: PMC6312476, DOI: 10.1002/ajmg.a.40632.Peer-Reviewed Original ResearchConceptsGerm line mutationsPredisposition to cancerSomatic malignancyOcular abnormalitiesCraniofacial dysmorphologyMalformation syndromePathogenetic etiologyRas/mitogen-activated protein kinasePathogenetic mechanismsEffects of dysregulationSomatic cancersOncogenic pathwaysCancerPhenotypic featuresRASopathiesMAPK pathwayRas pathwayNormal functionEncode componentsProtein kinaseNeurocognitive issuesExcellent modelPathwayMalignancyQuantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors
Stites E, Shaw A. Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors. CPT Pharmacometrics & Systems Pharmacology 2018, 7: 342-351. PMID: 29484842, PMCID: PMC5980551, DOI: 10.1002/psp4.12291.Peer-Reviewed Original ResearchConceptsRegulates Ras activitySystems biology approachBiology approachRas activationProtein turnoverKRAS-G12C covalent inhibitorsKRAS G12C inhibitorsSystems pharmacology analysisRasKRAS mutantDrug developmentG12C inhibitorsCovalent inhibitorsInhibitorsKRASMutantsPharmacological analysisMutationsKRAS G12C
2015
Use of Mechanistic Models to Integrate and Analyze Multiple Proteomic Datasets
Stites E, Aziz M, Creamer M, Von Hoff D, Posner R, Hlavacek W. Use of Mechanistic Models to Integrate and Analyze Multiple Proteomic Datasets. Biophysical Journal 2015, 108: 1819-1829. PMID: 25863072, PMCID: PMC4390817, DOI: 10.1016/j.bpj.2015.02.030.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorExperimentally detected interactionsPhosphotyrosine-binding domainSrc homology 2Recruitment of proteinsCell line-specific modelsProtein copy numbersProtein-protein interactionsCell signaling networksEpidermal growth factor receptor signalingCell linesWell-characterized roleCell line-specific differencesLow-affinity interactionsLine-specific differencesActivation of EGFR signalingMultiple cell linesLigand-stimulated activationAutophosphorylation sitesSignaling networksProteomic datasetsCopy numberHomolog 2EGFR signalingMap interactions
2013
Allosteric Activation of Functionally Asymmetric RAF Kinase Dimers
Hu J, Stites E, Yu H, Germino E, Meharena H, Stork P, Kornev A, Taylor S, Shaw A. Allosteric Activation of Functionally Asymmetric RAF Kinase Dimers. Cell 2013, 154: 1036-1046. PMID: 23993095, PMCID: PMC3844432, DOI: 10.1016/j.cell.2013.07.046.Peer-Reviewed Original ResearchMeSH KeywordsAllosteric RegulationAmino Acid MotifsAmino Acid SequenceAnimalsCell LineDimerizationEnzyme ActivationHumansMiceModels, MolecularMolecular Sequence DataMutationPhosphorylationProtein ConformationProtein KinasesProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-rafRaf KinasesSequence AlignmentTryptophanConceptsN-terminal phosphorylationReceiver kinaseRaf kinaseActivation-loop phosphorylationPhosphorylation of CRAFConstitutively active mutantCis-autophosphorylationRaf activationActive mutantActivated CRAFActive kinaseMechanism of activationKinase activityActive conformationKinasePhosphorylationControl cellsRafCRAFDimerMutantsRasActivityMEKBRAFChemical kinetic mechanistic models to investigate cancer biology and impact cancer medicine
Stites E. Chemical kinetic mechanistic models to investigate cancer biology and impact cancer medicine. Physical Biology 2013, 10: 026004. PMID: 23406820, DOI: 10.1088/1478-3975/10/2/026004.Peer-Reviewed Original ResearchConceptsBiochemical networksCancer biologyInvestigate cancer biologyDisrupt cellular processesAcquisition of mutationsCellular processesClinical management of cancer patientsMutated genesCancer medicineMolecular biologyExperimental biologyFeatures of cancerBiologyMutationsMechanistic modelExperimental approachGenesMolecular reactionsPace of progressKinetic mechanistic modelsCancerManagement of cancer patients
2012
The Response of Cancers to BRAF Inhibition Underscores the Importance of Cancer Systems Biology
Stites E. The Response of Cancers to BRAF Inhibition Underscores the Importance of Cancer Systems Biology. Science Signaling 2012, 5: pe46. PMID: 23074264, DOI: 10.1126/scisignal.2003354.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorBRAF(V600E) mutationAmount of epidermal growth factor receptorEpidermal growth factor receptor inhibitorsBRAF inhibitor vemurafenibColon cancer patientsGrowth factor receptorCancer systems biologyFunctional genomics approachDecreased negative feedbackMelanoma patientsClinical responseBRAF inhibitionInhibitor vemurafenibTreatment optionsColon cancerClinical evaluationFactor receptorCancer patientsCombined treatmentBRAF(V600EVemurafenibGenomic approachesSystems biologyCancerGenome-Wide Characterization of Pancreatic Adenocarcinoma Patients Using Next Generation Sequencing
Liang W, Craig D, Carpten J, Borad M, Demeure M, Weiss G, Izatt T, Sinari S, Christoforides A, Aldrich J, Kurdoglu A, Barrett M, Phillips L, Benson H, Tembe W, Braggio E, Kiefer J, Legendre C, Posner R, Hostetter G, Baker A, Egan J, Han H, Lake D, Stites E, Ramanathan R, Fonseca R, Stewart A, Von Hoff D. Genome-Wide Characterization of Pancreatic Adenocarcinoma Patients Using Next Generation Sequencing. PLOS ONE 2012, 7: e43192. PMID: 23071490, PMCID: PMC3468610, DOI: 10.1371/journal.pone.0043192.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaBase SequenceBRCA2 ProteinDNA RepairFemaleGene DosageGenome, HumanHigh-Throughput Nucleotide SequencingHumansMaleMetabolic Networks and PathwaysPancreatic NeoplasmsProto-Oncogene ProteinsProto-Oncogene Proteins c-mycProto-Oncogene Proteins p21(ras)Ras ProteinsSequence Analysis, RNATranscriptomeTumor Suppressor Protein p53ConceptsPancreatic adenocarcinoma patientsNext generation sequencingPancreatic adenocarcinomaGeneration sequencingSomatic eventsGenome-wide characterizationChromosomal copy number variantsCopy number variantsImproved therapeutic selectivityTumor suppressive pathwaysPancreatic adenocarcinoma tumorigenesisTumor-stroma interactionsKRAS signaling pathwaySequence dataTranscriptomic informationTumor/normal samplesEvaluate expression changesTranslocation eventsMultiple genesPoint mutationsRNA sequencingMapped readsPatient tumorsAdenocarcinoma patientsPathway analysisMathematical Investigation of How Oncogenic Ras Mutants Promote Ras Signaling
Stites E, Ravichandran K. Mathematical Investigation of How Oncogenic Ras Mutants Promote Ras Signaling. Methods In Molecular Biology 2012, 880: 69-85. PMID: 23361982, DOI: 10.1007/978-1-61779-833-7_5.Peer-Reviewed Original Research
2011
Mechanistic modeling to investigate signaling by oncogenic Ras mutants
Stites E, Ravichandran K. Mechanistic modeling to investigate signaling by oncogenic Ras mutants. WIREs Mechanisms Of Disease 2011, 4: 117-127. PMID: 21766467, DOI: 10.1002/wsbm.156.Peer-Reviewed Original ResearchConceptsCell signaling networksSignaling networksCancer phenotypeMutant Ras signalingAcquisition of mutationsRas signalingCell signalingBiochemistry of proteinsLevel of signalMutated genesExpression levelsBiochemical reaction mechanismsPhenotypeMechanistic modelInvestigated signalSignalGenesMutationsRasProteinCancerIndividual reactionsExpression