2025
FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma
Lubrano S, Cervantes-Villagrana R, Faraji F, Ramirez S, Sato K, Adame-Garcia S, Officer A, Arang N, Rigiracciolo D, Anguiano Quiroz P, Martini C, Wang Y, Ferguson F, Bacchiocchi A, Halaban R, Coma S, Holmen S, Pachter J, Aplin A, Gutkind J. FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma. Cancer Cell 2025, 43: 428-445.e6. PMID: 40020669, PMCID: PMC11903146, DOI: 10.1016/j.ccell.2025.02.001.Peer-Reviewed Original ResearchConceptsBRAF V600E melanomaFocal adhesion kinaseV600E melanomaFAK inhibitorActivated focal adhesion kinaseFocal adhesion kinase inhibitionRaf-MEKActivation of focal adhesion signalingFocal adhesion kinase inhibitorResistance to BRAFiSyngeneic mouse modelMAPK pathway inhibitionFocal adhesion signalingPro-apoptotic activityMelanoma patientsAdhesion signalingImmune therapyBRAF mutationsBRAFiTranscriptome analysisMelanomaMouse modelPathway inhibitionBRAFMelanoma cellsCrosstalk Between nNOS/NO and COX-2 Enhances Interferon-Gamma-Stimulated Melanoma Progression
Patel A, Tong S, Roosan M, Syed B, Awasthi A, Silverman R, Yang S. Crosstalk Between nNOS/NO and COX-2 Enhances Interferon-Gamma-Stimulated Melanoma Progression. Cancers 2025, 17: 477. PMID: 39941844, PMCID: PMC11816268, DOI: 10.3390/cancers17030477.Peer-Reviewed Original ResearchNeuronal nitric oxide synthaseIFN-gPro-tumorigenic activityCOX-2Human melanoma xenograft mouse modelMelanoma progressionMelanoma cellsFlow cytometryInduction of neuronal nitric oxide synthaseNeuronal nitric oxide synthase blockadeIn vivo antitumor efficacyMelanoma xenograft mouse modelMelanoma tumor microenvironmentLevels of PGE<sub>2</sub>PD-L1 expressionAnticancer immune responseMelanoma tumor growth in vivoCOX-2 expression levelsAnalysis of patientsInduction of COX-2Increased intracellular NO levelsSTAT3 inhibitor NapabucasinNitric oxideInhibited COX-2 expressionXenograft mouse model
2024
Single-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 responsesOvercoming melanin interference in melanocyte photodynamic therapy with a pyrene-derived two-photon photosensitizer
Juvekar V, Cao Y, Koh C, Lee D, Kwak S, Kim S, Park T, Park S, Liu Z, Kim H. Overcoming melanin interference in melanocyte photodynamic therapy with a pyrene-derived two-photon photosensitizer. Chemical Engineering Journal 2024, 493: 152796. DOI: 10.1016/j.cej.2024.152796.Peer-Reviewed Original ResearchPhotodynamic therapyPhotodynamic therapy efficacyPlasma membrane of melanoma cellsMelanoma cellsInhibition of tumor growthReactive oxygen speciesConventional photodynamic therapyTails of miceTreatment of skin diseasesTumor modelTreat melanomaTumor growthMelanin contentMulticellular tumor spheroidsSkin cancerMelanomaVisible light irradiationPDT efficacySkin diseasesMelanin interferenceVisible light excitationBroad absorption spectraChlorin e6ROS generation efficiencyTP-PDTCombined 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
Single cell profiling of tumour biopsies and heterogeneity in response of dedifferentiated melanoma.
Lim E, Lin Y, Pedersen B, Stewart A, Scolyer R, Long G, Yang J, Rizos H. Single cell profiling of tumour biopsies and heterogeneity in response of dedifferentiated melanoma. JCO Global Oncology 2023, 9: 64-64. DOI: 10.1200/go.2023.9.supplement_1.64.Peer-Reviewed Original ResearchResistance to MAPK inhibitionPro-inflammatory IL-6BRAF/MEK inhibitorsIL-6MAPK inhibitionTumor biopsiesAdvanced BRAF V600-mutant melanomaResponse to second-line treatmentTreated with immune checkpoint inhibitorsDT treatmentBRAF-mutant melanoma patientsResponse to MAPK inhibitionMelanoma cellsBRAF V600-mutant melanomaV600-mutant melanomaImmune checkpoint inhibitorsSecond-line treatmentTNFA signalingEx vivo treatmentElevated IL-6Increased IL-6Treated ex vivoDifferentiation stateImmune cell proportionsProportion of melanoma cells
2022
Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors.
Fenton S, Zannikou M, Ilut L, Fischietti M, Ji C, Oku C, Horvath C, Le Poole I, Bosenberg M, Bartom E, Kocherginsky M, Platanias L, Saleiro D. Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors. Molecular Cancer Research 2022, 21: 332-344. PMID: 36573964, PMCID: PMC10073316, DOI: 10.1158/1541-7786.mcr-22-0684.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsImmunosuppressive genesCheckpoint inhibitorsImmunostimulatory genesAnti-programmed cell death protein 1 therapyPharmacologic inhibitionIFNγ-induced expressionMelanoma cellsMajority of patientsTreatment of patientsTreatment of melanomaMelanoma tumor growthDrug target inhibitionICI therapyDurable responsesPatient survivalMetastatic melanomaPatient outcomesPoor survivalResponse rateTumor growthIFNγOverexpression of ULK1Context-dependent mannerMelanomaALDH1A1 overexpression in melanoma cells promotes tumor angiogenesis by activating the IL-8/Notch signaling cascade
Ciccone V, Terzuoli E, Ristori E, Filippelli A, Ziche M, Morbidelli L, Donnini S. ALDH1A1 overexpression in melanoma cells promotes tumor angiogenesis by activating the IL-8/Notch signaling cascade. International Journal Of Molecular Medicine 2022, 50: 99. PMID: 35656893, PMCID: PMC9186295, DOI: 10.3892/ijmm.2022.5155.Peer-Reviewed Original ResearchConceptsIL-8Endothelial cellsMelanoma cellsTumor cellsALDH1A1 expressionAngiogenic factorsAngiogenic featuresTumor microenvironmentCancer cellsPoor clinical outcomeHigher microvessel densityNumber of cancersPro-angiogenic phenotypeOverexpression of ALDH1A1ALDH1A1 overexpressionClinical outcomesCo-culture systemMicrovessel densityImmunodeficient miceNF-kBProangiogenic factorsMelanoma cancer cellsTumor angiogenesisMelanoma controlStromal cellsTowards rainbow portable Cytophone with laser diodes for global disease diagnostics
Jawad H, Yadem A, Menyaev Y, Sarimollaoglu M, Armstrong J, Watanabe F, Biris A, Stumhofer J, Nedosekin D, Suen J, Parikh S, Zharov V. Towards rainbow portable Cytophone with laser diodes for global disease diagnostics. Scientific Reports 2022, 12: 8671. PMID: 35606373, PMCID: PMC9126638, DOI: 10.1038/s41598-022-11452-w.Peer-Reviewed Original ResearchConceptsPlasmodium yoelii murine modelDetect infected cellsMalaria-infected erythrocytesDiagnosis of melanomaMalaria progressionSickle anemiaMurine modelDiagnosis of cancerMelanoma cellsEarly diagnosisCardiovascular disordersIn vivoEarly diagnosis of cancerInfected cellsIn vitroBlood backgroundDisease markersRed clotsMelanomaHemozoinMarkersSelectable markerBacteremiaCellsAnemiaTranscriptional profiling of macrophages in situ in metastatic melanoma reveals localization-dependent phenotypes and function
Martinek J, Lin J, Kim KI, Wang VG, Wu TC, Chiorazzi M, Boruchov H, Gulati A, Seeniraj S, Sun L, Marches F, Robson P, Rongvaux A, Flavell RA, George J, Chuang JH, Banchereau J, Palucka K. Transcriptional profiling of macrophages in situ in metastatic melanoma reveals localization-dependent phenotypes and function. Cell Reports Medicine 2022, 3: 100621. PMID: 35584631, PMCID: PMC9133468, DOI: 10.1016/j.xcrm.2022.100621.Peer-Reviewed Original ResearchConceptsMonocytes/macrophagesDendritic cellsMetastatic melanomaMelanoma cellsMetastatic cutaneous melanomaRegulation of toleranceSpecific transcriptional signatureTranscriptional profilingGene setsLaser capture microdissectionCell-based therapiesTranscriptional signatureCutaneous melanomaDC functionPatient outcomesMetastatic cancerTumor nestsTCGA cohortImmune functionCandidate biomarkersCD14Stromal macrophagesTumor siteTherapeutic opportunitiesAntigen captureSynthetic introns enable splicing factor mutation-dependent targeting of cancer cells
North K, Benbarche S, Liu B, Pangallo J, Chen S, Stahl M, Bewersdorf J, Stanley R, Erickson C, Cho H, Pineda J, Thomas J, Polaski J, Belleville A, Gabel A, Udy D, Humbert O, Kiem H, Abdel-Wahab O, Bradley R. Synthetic introns enable splicing factor mutation-dependent targeting of cancer cells. Nature Biotechnology 2022, 40: 1103-1113. PMID: 35241838, PMCID: PMC9288984, DOI: 10.1038/s41587-022-01224-2.Peer-Reviewed Original ResearchConceptsBreast cancerExpression of herpes simplex virus thymidine kinaseHerpes simplex virus thymidine kinaseCancer cellsPancreatic cancer cells in vitroWild-type cellsCancer cells in vitroCancer gene therapyTargeting of cancer cellsTumor-specific changesUveal melanoma cellsTreatment in vivoSynthetic intronChange-of-function mutationsCells in vitroUveal melanomaSF3B1 mutationsHSV-tkGene therapyTumor cellsIsogenic wild-type cellsMelanoma cellsRNA splicing factorsCancerHost survivalInhibition of renalase drives tumour rejection by promoting T cell activation
Guo X, Jessel S, Qu R, Kluger Y, Chen TM, Hollander L, Safirstein R, Nelson B, Cha C, Bosenberg M, Jilaveanu LB, Rimm D, Rothlin CV, Kluger HM, Desir GV. Inhibition of renalase drives tumour rejection by promoting T cell activation. European Journal Of Cancer 2022, 165: 81-96. PMID: 35219026, PMCID: PMC8940682, DOI: 10.1016/j.ejca.2022.01.002.Peer-Reviewed Original ResearchConceptsPD-1 inhibitorsMurine melanoma modelMelanoma-bearing miceMelanoma modelTumor microenvironmentTumor rejectionCell death protein 1 (PD-1) inhibitorsAnti-PD-1 activityEnhanced T cell infiltrationT cell-dependent fashionMelanoma cellsMelanoma tumor regressionPreclinical melanoma modelsT cell infiltrationNatural killer cellsForkhead box P3Expression of IFNγWild-type miceProtein 1 inhibitorT cell activationTumor cell contentWild-type melanoma cellsCD4 cellsAdvanced melanomaAntibody treatment
2021
3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype
Pizzurro GA, Liu C, Bridges K, Alexander AF, Huang A, Baskaran JP, Ramseier J, Bosenberg MW, Mak M, Miller-Jensen K. 3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype. Cancers 2021, 13: 4579. PMID: 34572807, PMCID: PMC8471848, DOI: 10.3390/cancers13184579.Peer-Reviewed Original ResearchTumor-associated macrophagesMelanoma tumor microenvironmentTumor microenvironmentTumor-promoting phenotypeAnti-tumor activityImmunosuppressive stateDisease progressionCo-culture systemImmune responseImmune activitySecretion profileDirect cell-cell interactionsMelanoma tumorsStromal componentsMacrophage transitionStromal cellsTumor cellsMelanoma cellsESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3
Coppo R, Orso F, Virga F, Dalmasso A, Baruffaldi D, Nie L, Clapero F, Dettori D, Quirico L, Grassi E, Defilippi P, Provero P, Valdembri D, Serini G, Sadeghi MM, Mazzone M, Taverna D. ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3. Cancer Letters 2021, 510: 13-23. PMID: 33862151, PMCID: PMC8581997, DOI: 10.1016/j.canlet.2021.04.005.Peer-Reviewed Original Research
2020
Abstract 5509: Breaking the paradox breakers - RAF inhibitor mechanisms
Mendiratta G, McFall T, Stites E. Abstract 5509: Breaking the paradox breakers - RAF inhibitor mechanisms. Cancer Research 2020, 80: 5509-5509. DOI: 10.1158/1538-7445.am2020-5509.Peer-Reviewed Original ResearchSW48 colon cancer cellsMechanism of PAColon cancer cellsParadoxical activationRaf activationAmerican Association for Cancer ResearchATP-competitive inhibitorsDimer stabilityDownstream signalingUpstream mutationsOnco-proteinRafInhibitor mechanismCancer cellsV600 mutationMutationsRegulatory processesDriver mutationsMelanoma cellsSide effectsCombined treatmentPotential PAProteinDrug bindingNo PA19. PLEKHA5 REGULATES TUMOR GROWTH IN METASTATIC MELANOMA
Oria V, Zhang H, Zhu H, Deng G, Zito C, Rane C, Zhang S, Weiss S, Tran T, Adeniran A, Zhang F, Zhou J, Kluger Y, Bosenberg M, Kluger H, Jilaveanu L. 19. PLEKHA5 REGULATES TUMOR GROWTH IN METASTATIC MELANOMA. Neuro-Oncology Advances 2020, 2: ii3-ii3. PMCID: PMC7401364, DOI: 10.1093/noajnl/vdaa073.009.Peer-Reviewed Original ResearchMelanoma brain metastasesBrain metastasesTumor growthPI3K/Akt/mTORCell cycle transitionAkt/mTORGrowth of tumorsS cell cycle transitionPhosphorylation of AktMelanoma patientsPoor prognosisNovel drug targetsPatient populationRegulation of PDCD4Metastatic melanomaUnique cohortXenograft modelClinical relevanceNude miceMetastasisCycle transitionMelanomaBrain developmentKey mediatorMelanoma cells
2019
Pathology of B cell and neutrophil infiltration in the YUMMER1.7 mouse model of spontaneous melanoma tumor regression
Blenman K, Wang J, Cowper S, Bosenberg M. Pathology of B cell and neutrophil infiltration in the YUMMER1.7 mouse model of spontaneous melanoma tumor regression. The Journal Of Immunology 2019, 202: 136.25-136.25. DOI: 10.4049/jimmunol.202.supp.136.25.Peer-Reviewed Original ResearchB cellsMelanoma cellsTumor regressionPlasmablasts/plasma cellsTumor-infiltrating B cellsLonger progression-free survivalMelanoma tumor regressionProgression-free survivalAdaptive immune responsesB cell numbersNeutrophil extracellular trapsNeutrophil infiltrationImmunotherapy treatmentSpontaneous regressionMetastatic melanomaAdverse reactionsGeographic necrosisImmune cellsNeutrophil responseHistological changesExtracellular trapsPlasma cellsImmune responseTherapy showTumor massA novel anti-melanoma SRC-family kinase inhibitor
Halaban R, Bacchiocchi A, Straub R, Cao J, Sznol M, Narayan D, Allam A, Krauthammer M, Mansour TS. A novel anti-melanoma SRC-family kinase inhibitor. Oncotarget 2019, 10: 2237-2251. PMID: 31040916, PMCID: PMC6481345, DOI: 10.18632/oncotarget.26787.Peer-Reviewed Original ResearchSrc family kinase inhibitorMAPK inhibitorTranscription factor MITFPatient-derived melanoma cellsPI3K activityKinase inhibitorsSynergistic growth inhibitionGrowth arrestMelanoma cell linesK activityProteolytic degradationCell linesERBB2 inhibitionOncogene expressionMelanoma therapyTumor growthDrug resistanceMelanoma cellsGrowth inhibitionAlternative targetsActivity leadInhibitorsPP2ASHP2InhibitionPathology of spontaneous and immunotherapy‐induced tumor regression in a murine model of melanoma
Blenman KRM, Wang J, Cowper S, Bosenberg M. Pathology of spontaneous and immunotherapy‐induced tumor regression in a murine model of melanoma. Pigment Cell & Melanoma Research 2019, 32: 448-457. PMID: 30702217, PMCID: PMC6500596, DOI: 10.1111/pcmr.12769.Peer-Reviewed Original ResearchConceptsTumor regressionB cellsMelanoma cellsNeutrophil extracellular trapsNeutrophil countAdverse reactionsGeographic necrosisNeutrophil responseExtracellular trapsHistological changesPlasma cellsMurine modelHost responseTumor microenvironmentImmunotherapyNeutrophilsTumorsRegression modelsCellsRegressionLike formationImmunocompetentPlasmablastsEpithelioidMelanoma
2017
MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway
Janostiak R, Rauniyar N, Lam TT, Ou J, Zhu LJ, Green MR, Wajapeyee N. MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway. Cell Reports 2017, 21: 2829-2841. PMID: 29212029, PMCID: PMC5726781, DOI: 10.1016/j.celrep.2017.11.033.Peer-Reviewed Original ResearchConceptsMaternal embryonic leucine zipper kinaseMelanoma growthSkin cancer-related deathsMelanoma cellsNF-κB pathway activityMAPK pathwayCancer-related deathNF-κB pathwayEmbryonic leucine zipper kinaseLeucine zipper kinaseMELK knockdownCurrent therapiesMELK inhibitionImportant downstream mediatorShort-term benefitsPharmacological inhibitionTranscription factor E2F1Downstream mediatorBRAFV600E inhibitorsSequestosome 1Pathway activityMELK functionMediatorsCell culturesInhibition
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