2022
STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer
Wang Q, Bergholz JS, Ding L, Lin Z, Kabraji SK, Hughes ME, He X, Xie S, Jiang T, Wang W, Zoeller JJ, Kim HJ, Roberts TM, Konstantinopoulos PA, Matulonis UA, Dillon DA, Winer EP, Lin NU, Zhao JJ. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nature Communications 2022, 13: 3022. PMID: 35641483, PMCID: PMC9156717, DOI: 10.1038/s41467-022-30568-1.Peer-Reviewed Original ResearchConceptsAnti-tumor immunityBreast cancerPARP inhibitorsSTING agonistsBRCA-mutant breast cancerTumor cellsAnti-tumor stateAdvanced ovarian tumorsCell-mediated suppressionType I IFN responseTumor-associated macrophagesInnate immune suppressionI IFN responseBreast tumor cellsTreatment landscapePro-tumor macrophagesImmune suppressionOvarian tumorsImmune cellsBRCA mutationsSystemic administrationT cellsMouse modelTherapeutic benefitBreast tumors
2017
CDK4/6 inhibition triggers anti-tumour immunity
Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, Hoog J, Ellis MJ, Ma CX, Ramm S, Krop IE, Winer EP, Roberts TM, Kim HJ, McAllister SS, Zhao JJ. CDK4/6 inhibition triggers anti-tumour immunity. Nature 2017, 548: 471-475. PMID: 28813415, PMCID: PMC5570667, DOI: 10.1038/nature23465.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigen PresentationBiological MimicryBreast NeoplasmsCell Cycle CheckpointsCell Line, TumorCell ProliferationCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Disease Models, AnimalFemaleHumansInterferonsMicePhosphorylationProtein Kinase InhibitorsRepressor ProteinsRNA, Double-StrandedSignal TransductionT-Lymphocytes, RegulatoryTranscriptomeViruses
2016
Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases
Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, Luu V, Marco E, Ramkissoon LA, Kang YJ, Hayashi M, Nguyen QD, Ligon AH, Du R, Claus EB, Alexander BM, Yuan GC, Wang ZC, Iglehart JD, Krop IE, Roberts TM, Winer EP, Lin NU, Ligon KL, Zhao JJ. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nature Medicine 2016, 22: 723-726. PMID: 27270588, PMCID: PMC4938731, DOI: 10.1038/nm.4120.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAminopyridinesAnimalsAntineoplastic AgentsApoptosisBrain NeoplasmsBreast NeoplasmsCarrier ProteinsCaspase 3Cell Cycle ProteinsDNA RepairDrug Resistance, NeoplasmDrug Therapy, CombinationEukaryotic Initiation FactorsEverolimusFemaleGene Expression ProfilingGenomic InstabilityHumansImmunohistochemistryKi-67 AntigenMagnetic Resonance ImagingMechanistic Target of Rapamycin Complex 1MiceMice, SCIDMolecular Targeted TherapyMorpholinesMultiprotein ComplexesNeoplasm TransplantationPhosphoinositide-3 Kinase InhibitorsPhosphoproteinsPhosphorylationReceptor, ErbB-2Remission InductionTOR Serine-Threonine KinasesXenograft Model Antitumor AssaysConceptsBreast cancer brain metastasesCancer brain metastasesBrain metastasesHER2-positive breast cancer brain metastasesOrthotopic patient-derived xenograftsPI3KPatient-derived xenograftsDurable remissionsTherapeutic responseMouse modelCombined inhibitionCombination inhibitionMetastasisInhibitionRemissionXenograftsMiceOvercoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors
Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, Ramm S, Palmer AC, Yuzugullu H, Varadan V, Tuck D, Harris LN, Wong KK, Liu XS, Sicinski P, Winer EP, Krop IE, Zhao JJ. Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell 2016, 29: 255-269. PMID: 26977878, PMCID: PMC4794996, DOI: 10.1016/j.ccell.2016.02.006.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Disease Models, AnimalDrug Resistance, NeoplasmErbB ReceptorsFemaleHumansMechanistic Target of Rapamycin Complex 1MiceMice, NudeMice, TransgenicMultiprotein ComplexesNeoplasm Recurrence, LocalPhosphorylationProtein Kinase InhibitorsReceptor, ErbB-2TOR Serine-Threonine KinasesTumor Suppressor ProteinsConceptsHER2-positive breast cancerCDK4/6 inhibitorsBreast cancerEGFR/HER2Patient-derived xenograft tumorsTransgenic mouse modelInhibition of CDK4/6Tumor recurrenceXenograft tumorsMouse modelPotent suppressionTransgenic modelClinical specimensTherapeutic resistanceDual inhibitionMediate resistanceHER2CancerTSC2 phosphorylationG1 arrestCellular senescenceTherapyRb phosphorylationTumorsCDK4/6
2015
PIK3CAH1047R- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling
Cheng H, Liu P, Ohlson C, Xu E, Symonds L, Isabella A, Muller WJ, Lin NU, Krop IE, Roberts TM, Winer EP, Arteaga CL, Zhao JJ. PIK3CAH1047R- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene 2015, 35: 2961-2970. PMID: 26640141, PMCID: PMC4896860, DOI: 10.1038/onc.2015.377.Peer-Reviewed Original ResearchConceptsBreast cancerPIK3CA mutationsMammary tumorsHER2 amplification/overexpressionHER2-positive breast cancerHER2-positive cancersPrimary mammary tumorsHER2/HER3PIK3CA-activating mutationsHER2/neuHuman breast cancerEffective treatment approachAmplification/overexpressionCompound mouse modelMEK-ERK signalingMouse mammary glandWorse prognosisCombination therapyMammary tumorigenesisMouse modelMutant PIK3CATreatment approachesHER2Combined inhibitionCompensatory activationPI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers
Wang Q, Liu P, Spangle JM, Von T, Roberts TM, Lin NU, Krop IE, Winer EP, Zhao JJ. PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene 2015, 35: 3607-3612. PMID: 26500061, PMCID: PMC4846581, DOI: 10.1038/onc.2015.406.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorCell SurvivalClass I Phosphatidylinositol 3-KinasesDrug Resistance, NeoplasmFemaleHumansLapatinibMammary Neoplasms, ExperimentalMice, KnockoutMolecular Targeted TherapyPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseQuinazolinesReceptor, ErbB-2Signal TransductionThiazolesTumor BurdenXenograft Model Antitumor AssaysConceptsBreast tumorsP110β inhibitorsHuman epidermal growth factor receptor 2 (HER2) amplificationP110α inhibitionPTEN lossInhibition of HER2Treatment of HER2Human cancersPI3K pathway activationPTEN-deficient breast cancersGenetic mouse modelsPI3K/Akt signalingPTEN-deficient tumorsPI3K/AktDual HER2Therapeutic regimenHER2 inhibitionPIK3CA mutationsTumor regressionBreast cancerMouse modelXenograft modelHER2Null tumorsHER2 activation