2024
Mechanism of Hyperactive PLCγ1 Signaling in T-Cell Leukemia/Lymphoma
Zeng L, Zhang X, Xiong Y, Hajicek N, Sondek J, Su X. Mechanism of Hyperactive PLCγ1 Signaling in T-Cell Leukemia/Lymphoma. Blood 2024, 144: 48-48. DOI: 10.1182/blood-2024-193065.Peer-Reviewed Original ResearchHDACi resistancePeripheral T-cell lymphomaCutaneous T-cell lymphomaAdult T-cell leukemia/lymphomaLiquid-liquid phase separationT-cell lymphomaT-cell leukemia/lymphomaT cell proliferationHistone deacetylasesTotal internal reflection fluorescenceT cellsTCR signalingDrug resistanceDysregulation of LLPSWild typeMolecular mechanismsAberrant protein aggregationInhibitor resistanceResistance to HDAC inhibitorsMemory T cell developmentT cell receptor signalingActivation of T cellsPromote T cell proliferationT-cell malignanciesBcl-2 expressionSingle-cell RNA sequencing reveals melanoma cell state-dependent heterogeneity of response to MAPK inhibitors
Lim S, Lin Y, Lee J, Pedersen B, Stewart A, Scolyer R, Long G, Yang J, Rizos H. Single-cell RNA sequencing reveals melanoma cell state-dependent heterogeneity of response to MAPK inhibitors. EBioMedicine 2024, 107: 105308. PMID: 39216232, PMCID: PMC11402938, DOI: 10.1016/j.ebiom.2024.105308.Peer-Reviewed Original ResearchMelanoma cellsTranscriptional cell statesTreatment responseSingle-cell RNA sequencingResponse to MAPK inhibitorsPlasticity of melanoma cellsBRAF/MEK inhibitor treatmentImmunotherapy-resistant tumorsMelanoma Institute AustraliaNational Health and Medical Research Council of AustraliaImpact treatment responseMelanoma cell statesPro-inflammatory signalingNational Health and Medical Research CouncilCell statesPro-inflammatory IL6Melanoma tumorsHeterogeneous cancerInhibitor resistanceInhibitor treatmentMelanomaBRAF/MEKRNA sequencingMAPK inhibitorStudy treatment responsesCombined BET and MEK Inhibition synergistically suppresses melanoma by targeting YAP1
Hu R, Hou H, Li Y, Zhang M, Li X, Chen Y, Guo Y, Sun H, Zhao S, Liao M, Cao D, Yan Q, Chen X, Yin M. Combined BET and MEK Inhibition synergistically suppresses melanoma by targeting YAP1. Theranostics 2024, 14: 593-607. PMID: 38169595, PMCID: PMC10758063, DOI: 10.7150/thno.85437.Peer-Reviewed Original ResearchConceptsMEK inhibitor resistanceMEK inhibitor trametinibTrametinib treatmentInhibitor resistanceInhibitor trametinibMelanoma patientsYAP1 expressionMEK inhibitionBRAF-mutant melanoma patientsResistance to MEK inhibitionYAP1 inhibitionResistance to trametinibMelanoma growth <i>inInhibition of BRD4Trametinib resistanceAntitumor effectMelanoma growthTrametinibNHWD-870YAP1 inhibitorDrug resistanceMelanomaMelanoma samplesMelanoma cellsBRD4 depletion
2023
Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer
de Miguel F, Gentile C, Feng W, Silva S, Sankar A, Exposito F, Cai W, Melnick M, Robles-Oteiza C, Hinkley M, Tsai J, Hartley A, Wei J, Wurtz A, Li F, Toki M, Rimm D, Homer R, Wilen C, Xiao A, Qi J, Yan Q, Nguyen D, Jänne P, Kadoch C, Politi K. Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer. Cancer Cell 2023, 41: 1516-1534.e9. PMID: 37541244, PMCID: PMC10957226, DOI: 10.1016/j.ccell.2023.07.005.Peer-Reviewed Original ResearchConceptsMammalian SWI/SNF chromatinSWI/SNF chromatinMSWI/SNF complexesGenome-wide localizationGene regulatory signaturesNon-genetic mechanismsEpithelial cell differentiationEGFR-mutant cellsChromatin accessibilitySNF complexCellular programsRegulatory signaturesTKI-resistant lung cancerGene targetsKinase inhibitor resistanceCell differentiationMesenchymal transitionTKI resistancePharmacologic disruptionTyrosine kinase inhibitor resistanceCell proliferationChromatinInhibitor resistanceEGFR-mutant lungKinase inhibitors
2022
Keeping RelApse in Chk: molecular mechanisms of Chk1 inhibitor resistance in lymphoma
Black E, Joo Y, Kabeche L. Keeping RelApse in Chk: molecular mechanisms of Chk1 inhibitor resistance in lymphoma. Biochemical Journal 2022, 479: 2345-2349. PMID: 36416754, PMCID: PMC9704517, DOI: 10.1042/bcj20220461.Peer-Reviewed Original ResearchConceptsReplication stressChk1 activityDNA damage response pathwayChk1 inhibitorsDNA replication stressInhibitor resistanceDamage response pathwayGenome instabilityPI3K/AktResponse pathwaysMolecular mechanismsNovel roleChk1Cancer therapyCancer developmentFemale fertilityDevelopment of resistancePathwayLethal levelsMultiple mechanismsAlternative pathwayNF-κBDrug resistanceIntriguing targetDisease states
2021
In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer
Lin ZP, Al Zouabi NN, Xu ML, Bowen NE, Wu TL, Lavi ES, Huang PH, Zhu YL, Kim B, Ratner ES. In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer. Scientific Reports 2021, 11: 8042. PMID: 33850183, PMCID: PMC8044145, DOI: 10.1038/s41598-021-87325-5.Peer-Reviewed Original ResearchConceptsEpithelial ovarian cancerSmall molecule inhibitorsPARP inhibitor resistancePARP inhibitorsBRCA mutationsOvarian cancerEOC cellsPoly ADP-ribose polymerase inhibitorsMolecule inhibitorsInhibitor resistanceADP-ribose polymerase inhibitorsTumor-bearing miceNovel small molecule inhibitorPARP inhibitor olaparibDefective homologous recombination (HR) repairEOC xenograftsClinical efficacySurvival timePutative small molecule inhibitorsInhibitor olaparibPolymerase inhibitorsHR repairInhibitorsCancerHomologous recombination repair
2019
Phosphorylation of human placental aromatase CYP19A1.
Ghosh D, Egbuta C, Kanyo J, Lam TT. Phosphorylation of human placental aromatase CYP19A1. Biochemical Journal 2019, 476: 3313-3331. PMID: 31652308, PMCID: PMC7069221, DOI: 10.1042/bcj20190633.Peer-Reviewed Original ResearchConceptsAromatase CYP19A1Protein-level regulationPhosphorylation/dephosphorylationMultiple phosphorylation sitesNon-genomic signaling pathwaysPost-translational modificationsNon-genomic signalingTranscriptional activatorPhosphorylation sitesProline residuesSignaling pathwaysHistidine residuesPhosphorylationLevel regulationAromatase inhibitor resistanceInhibitor resistanceMembrane interfaceRegulationReproductive systemStructural dataAromatase activityActive siteResiduesGenotoxic effectsSynaptic terminals
2018
Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling
Rukhlenko OS, Khorsand F, Krstic A, Rozanc J, Alexopoulos LG, Rauch N, Erickson KE, Hlavacek WS, Posner RG, Gómez-Coca S, Rosta E, Fitzgibbon C, Matallanas D, Rauch J, Kolch W, Kholodenko BN. Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling. Cell Systems 2018, 7: 161-179.e14. PMID: 30007540, PMCID: PMC6149545, DOI: 10.1016/j.cels.2018.06.002.Peer-Reviewed Original ResearchConceptsOncogenic RASERK signalingRAS/ERK pathwayRAF inhibitorsOncogenic Ras signalingMEK/ERKStructure-based modelingRAF inhibitor resistanceRAS mutant tumorsRas signalingPosttranslational modificationsRaf kinaseERK activityRAF dimerizationDrug-protein interactionsERK pathwayMultiple inhibitorsColony formationSignalingMutant NRASCell proliferationDrug designParadoxical activationInhibitor resistanceMechanistic dynamic model
2017
Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with β-blockers
Nilsson MB, Sun H, Diao L, Tong P, Liu D, Li L, Fan Y, Poteete A, Lim SO, Howells K, Haddad V, Gomez D, Tran H, Pena GA, Sequist LV, Yang JC, Wang J, Kim ES, Herbst R, Lee JJ, Hong WK, Wistuba I, Hung MC, Sood AK, Heymach JV. Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with β-blockers. Science Translational Medicine 2017, 9 PMID: 29118262, PMCID: PMC5870120, DOI: 10.1126/scitranslmed.aao4307.Peer-Reviewed Original ResearchMeSH KeywordsAdrenergic beta-AntagonistsAfatinibAMP-Activated Protein Kinase KinasesCarcinoma, Non-Small-Cell LungCell Line, TumorCyclic AMP Response Element-Binding ProteinDrug Resistance, NeoplasmEpinephrineErbB ReceptorsHumansInterleukin-6Lung NeoplasmsMutationNorepinephrineProtein Kinase CProtein Kinase InhibitorsProtein Serine-Threonine KinasesQuinazolinesReceptors, Adrenergic, betaSignal TransductionXenograft Model Antitumor AssaysConceptsNon-small cell lung cancerEGFR inhibitor resistanceΒ-blockersInhibitor resistanceStress hormonesLiver kinase B1Epidermal growth factor receptor tyrosine kinase inhibitor resistanceLower IL-6 concentrationsΒ-blocker useIL-6 concentrationsIL-6 inhibitionCell lung cancerTyrosine kinase inhibitor resistanceEGFR-TKI resistanceInterleukin-6 expressionKinase inhibitor resistanceChronic stress hormonesNSCLC patientsEGFR-TKIIL-6Lung cancerAR activationWorse outcomesNSCLC cellsTKI resistance
2015
The broad‐spectrum receptor tyrosine kinase inhibitor dovitinib suppresses growth of BRAF‐mutant melanoma cells in combination with other signaling pathway inhibitors
Langdon CG, Held MA, Platt JT, Meeth K, Iyidogan P, Mamillapalli R, Koo AB, Klein M, Liu Z, Bosenberg MW, Stern DF. The broad‐spectrum receptor tyrosine kinase inhibitor dovitinib suppresses growth of BRAF‐mutant melanoma cells in combination with other signaling pathway inhibitors. Pigment Cell & Melanoma Research 2015, 28: 417-430. PMID: 25854919, PMCID: PMC5215495, DOI: 10.1111/pcmr.12376.Peer-Reviewed Original ResearchConceptsBRAF-mutant melanomaBRAF inhibitorsCell linesCombination of dovitinibBRAF inhibitor treatmentBRAF mutant melanoma cellsBRAF inhibitor resistanceColorectal carcinoma cell linesBRAF-mutant melanoma cell linesMelanoma cell linesCarcinoma cell linesMetastatic melanomaEffective therapyWild-type BRAF cellsInhibitor treatmentAgent inhibitsPathway inhibitorDovitinibInhibitor resistanceMelanoma cellsMelanomaSecond agentInhibitorsTreatmentA Functional Landscape of Resistance to ALK Inhibition in Lung Cancer
Wilson FH, Johannessen CM, Piccioni F, Tamayo P, Kim JW, Van Allen EM, Corsello SM, Capelletti M, Calles A, Butaney M, Sharifnia T, Gabriel SB, Mesirov JP, Hahn WC, Engelman JA, Meyerson M, Root DE, Jänne PA, Garraway LA. A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer. Cancer Cell 2015, 27: 397-408. PMID: 25759024, PMCID: PMC4398996, DOI: 10.1016/j.ccell.2015.02.005.Peer-Reviewed Original ResearchConceptsFunctional genetic studiesG protein-coupled receptorsResistance driversALK inhibitionFunctional landscapeGenetic studiesLung cancer cellsALK inhibitor resistanceResistance pathwaysMechanisms of resistanceReceptor familyPKC activationPurinergic receptor familyPKC inhibitionCrizotinib-resistant ALKCancer cellsInhibitor resistanceGene signatureDependent mechanismLung cancerLung tumorsALK inhibitorsInhibitionALKMechanism
2013
Can Inhibitor-Resistant Substitutions in the Mycobacterium tuberculosis β-Lactamase BlaC Lead to Clavulanate Resistance?: a Biochemical Rationale for the Use of β-Lactam–β-Lactamase Inhibitor Combinations
Kurz S, Wolff K, Hazra S, Bethel C, Hujer A, Smith K, Xu Y, Tremblay L, Blanchard J, Nguyen L, Bonomo R. Can Inhibitor-Resistant Substitutions in the Mycobacterium tuberculosis β-Lactamase BlaC Lead to Clavulanate Resistance?: a Biochemical Rationale for the Use of β-Lactam–β-Lactamase Inhibitor Combinations. Antimicrobial Agents And Chemotherapy 2013, 57: 6085-6096. PMID: 24060876, PMCID: PMC3837893, DOI: 10.1128/aac.01253-13.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionAntitubercular Agentsbeta-Lactamase Inhibitorsbeta-LactamasesClavulanic AcidDrug Therapy, CombinationEscherichia coliExtensively Drug-Resistant TuberculosisGene ExpressionHumansMeropenemMicrobial Sensitivity TestsMutagenesis, Site-DirectedMycobacterium tuberculosisProtein EngineeringRecombinant ProteinsThienamycinsConceptsInhibitor combinationsResistance to clavulanic acidMultidrug resistanceDrug resistanceClavulanic acidExtensively drug-resistant M. tuberculosis strainsEmergence of multidrug resistanceCombination of meropenemDrug-resistant M. tuberculosis strainsPresence of ampicillinAmino acid residuesExtensively drug-resistantM. tuberculosis strainsNovel treatment strategiesInhibition of growthPotential therapeutic targetTreatment regimensTherapeutic modalitiesTreatment strategiesInhibitor resistanceM. tuberculosisEnzymatic assayImpaired inhibitionTherapeutic targetAcid resistanceAn Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance
Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK, Nilsson MB, Gudikote J, Tran H, Cardnell RJ, Bearss DJ, Warner SL, Foulks JM, Kanner SB, Gandhi V, Krett N, Rosen ST, Kim ES, Herbst RS, Blumenschein GR, Lee JJ, Lippman SM, Ang KK, Mills GB, Hong WK, Weinstein JN, Wistuba II, Coombes KR, Minna JD, Heymach JV. An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance. Clinical Cancer Research 2013, 19: 279-290. PMID: 23091115, PMCID: PMC3567921, DOI: 10.1158/1078-0432.ccr-12-1558.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxl Receptor Tyrosine KinaseCarcinoma, Non-Small-Cell LungCell Line, TumorCluster AnalysisDrug Resistance, NeoplasmEpithelial-Mesenchymal TransitionErbB ReceptorsGene Expression ProfilingHumansLung NeoplasmsMiceNeoplasm MetastasisPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProteomeProteomicsProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesRecurrenceReproducibility of ResultsConceptsEpithelial-mesenchymal transitionPotential therapeutic targetEGFR inhibitor resistanceTherapeutic targetEMT signatureInhibitor resistanceMesenchymal transition gene signatureMesenchymal cellsCell linesBiomarker-Integrated ApproachesPI3K/Akt pathway inhibitorNon-small cell lung carcinoma cell lineEGFR mutation statusReceptor tyrosine kinase AXLNSCLC cell linesPI3K/Akt inhibitorCell lung carcinoma cell lineGene expression profilesTyrosine kinase AXLLung carcinoma cell linePI3K inhibitorsDrug response analysisAkt pathway inhibitorCarcinoma cell linesErlotinib resistance
2010
Antiretroviral medication adherence and class-specific resistance in a large prospective clinical trial
Gardner EM, Hullsiek KH, Telzak EE, Sharma S, Peng G, Burman WJ, MacArthur RD, Chesney M, Friedland G, Mannheimer SB. Antiretroviral medication adherence and class-specific resistance in a large prospective clinical trial. AIDS 2010, 24: 395-403. PMID: 20099399, PMCID: PMC2886717, DOI: 10.1097/qad.0b013e328335cd8a.Peer-Reviewed Original ResearchConceptsInitial virological failureCumulative adherenceVirological failureMedian timeNucleoside reverse transcriptase inhibitor resistanceProspective clinical trial dataInhibitor strategiesLarge prospective clinical trialsReverse transcriptase inhibitor resistanceInhibitor resistanceAntiretroviral-naive participantsProspective clinical trialsCox regression analysisTranscriptase inhibitor resistanceAntiretroviral medication adherenceProtease inhibitor resistanceClinical trial dataProtease inhibitorsMedication resistanceAntiretroviral therapyHIV RNANNRTI resistanceMedication adherenceClinical trialsGenotypic resistance
1996
HIV-1 Reverse Transcriptase Resistance to Nonnucleoside Inhibitors †
Spence R, Anderson K, Johnson K. HIV-1 Reverse Transcriptase Resistance to Nonnucleoside Inhibitors †. Biochemistry 1996, 35: 1054-1063. PMID: 8547241, DOI: 10.1021/bi952058+.Peer-Reviewed Original ResearchConceptsMutant enzymesPre-steady-state techniquesSingle nucleotide incorporationWild-type complexMaximum incorporation rateNucleotide incorporationEnzyme complexDuplex DNAAffinity 2Cysteine mutationsTwo-step bindingWild-typeConformational changesDecreased affinityEnzymePresence of nevirapineInhibitor resistanceMutationsIncorporation rateY181C mutationWild-type RTReverse transcriptaseHIV-1NevirapineY181C
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