2019
Small molecule combats cancer-causing KRAS protein at last
Herbst RS, Schlessinger J. Small molecule combats cancer-causing KRAS protein at last. Nature 2019, 575: 294-295. PMID: 31705127, DOI: 10.1038/d41586-019-03242-8.Peer-Reviewed Original Research
2015
Co-occurring Genomic Alterations Define Major Subsets of KRAS-Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities
Skoulidis F, Byers LA, Diao L, Papadimitrakopoulou VA, Tong P, Izzo J, Behrens C, Kadara H, Parra ER, Canales JR, Zhang J, Giri U, Gudikote J, Cortez MA, Yang C, Fan Y, Peyton M, Girard L, Coombes KR, Toniatti C, Heffernan TP, Choi M, Frampton GM, Miller V, Weinstein JN, Herbst RS, Wong KK, Zhang J, Sharma P, Mills GB, Hong WK, Minna JD, Allison JP, Futreal A, Wang J, Wistuba II, Heymach JV. Co-occurring Genomic Alterations Define Major Subsets of KRAS-Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities. Cancer Discovery 2015, 5: 860-877. PMID: 26069186, PMCID: PMC4527963, DOI: 10.1158/2159-8290.cd-14-1236.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdenocarcinoma of LungAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesCell Line, TumorCluster AnalysisDNA-Binding ProteinsGene ExpressionGene Expression ProfilingGenetic VariationGenomicsHumansInflammationLung NeoplasmsMutationOxidative StressPrognosisProtein Serine-Threonine KinasesRas ProteinsSignal TransductionTranscription FactorsTumor Suppressor ProteinsConceptsKRAS-mutant lung adenocarcinomaCo-occurring genomic alterationsLung adenocarcinomaDistinct biologyTherapeutic vulnerabilitiesSTK11/LKB1Hsp90 inhibitor therapyRelapse-free survivalDrug sensitivity patternsGenomic alterationsCDKN2A/BKC tumorsInflammatory markersMucinous histologyImmune markersImmune profilePD-L1AdenocarcinomaSensitivity patternMajor subsetNKX2-1 transcription factorLow expressionTumorsGenetic alterationsEffector molecules
2014
A RAS Renaissance: Emerging Targeted Therapies for KRAS-Mutated Non–Small Cell Lung Cancer
Vasan N, Boyer JL, Herbst RS. A RAS Renaissance: Emerging Targeted Therapies for KRAS-Mutated Non–Small Cell Lung Cancer. Clinical Cancer Research 2014, 20: 3921-3930. PMID: 24893629, PMCID: PMC5369356, DOI: 10.1158/1078-0432.ccr-13-1762.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerCell lung cancerLung cancerClinical trialsNew clinical trialsEarly clinical trialsPathway-targeted therapiesTargeted therapyMechanism of activityNovel targetCancerDruggable targetsTherapyDisappointing resultsHuman cancersSmall-molecule screenFarnesyltransferase inhibitorsRAS gene productsNew RATrialsPharmaceutical companiesNumerous oncogenesNumerous studiesSynthetic lethality screenPathwayEGFR biomarkers predict benefit from vandetanib in combination with docetaxel in a randomized phase III study of second-line treatment of patients with advanced non-small cell lung cancer
Heymach JV, Lockwood SJ, Herbst RS, Johnson BE, Ryan AJ. EGFR biomarkers predict benefit from vandetanib in combination with docetaxel in a randomized phase III study of second-line treatment of patients with advanced non-small cell lung cancer. Annals Of Oncology 2014, 25: 1941-1948. PMID: 25057173, PMCID: PMC4176452, DOI: 10.1093/annonc/mdu269.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerSecond-line treatmentProgression-free survivalAdvanced non-small cell lung cancerRandomized phase III studyPhase III studyCell lung cancerMutation-positive tumorsEGFR mutationsIII studyTumor samplesClinical benefitLung cancerSecond-line non-small cell lung cancerEGFR FISH-positive tumorsEGFR mutation-positive tumorsEpidermal growth factor receptor (EGFR) gene mutationsObjective response rateRelative clinical benefitFirst-line chemotherapyObjective tumor responseProtein expressionOverall study populationGene mutationsPretreatment tumor samples
2013
Clinical and Biomarker Outcomes of the Phase II Vandetanib Study from the BATTLE Trial
Tsao AS, Liu S, Lee JJ, Alden CM, Blumenschein GR, Herbst R, Davis SE, Kim E, Lippman S, Heymach J, Tran H, Tang X, Wistuba I, Hong WK. Clinical and Biomarker Outcomes of the Phase II Vandetanib Study from the BATTLE Trial. Journal Of Thoracic Oncology 2013, 8: 658-661. PMID: 23584298, PMCID: PMC5118909, DOI: 10.1097/jto.0b013e31828d08ae.Peer-Reviewed Original ResearchMeSH KeywordsAcute-Phase ProteinsAgedAntineoplastic AgentsBiomarkers, TumorCarcinoma, Non-Small-Cell LungDisease-Free SurvivalFemaleGene AmplificationGenes, erbB-1HumansInterleukin-9Kaplan-Meier EstimateLipocalin-2LipocalinsLung NeoplasmsMaleMiddle AgedMutationPiperidinesProportional Hazards ModelsProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)QuinazolinesRas ProteinsTNF-Related Apoptosis-Inducing LigandConceptsDisease control rateWorse OSShorter PFSControl rateMutation patientsDual epidermal growth factor receptorVascular endothelial growth factor receptor inhibitionLung Cancer Elimination (BATTLE) trialNeutrophil gelatinase-associated lipocalinCell lung cancer patientsGrowth factor receptor inhibitionPhase II trialGelatinase-associated lipocalinLung cancer patientsTumor core biopsiesSerum biomarker analysisEGFR mutation patientsEpidermal growth factor receptorEGFR gene amplificationApoptosis-inducing ligandGrowth factor receptorMedian PFSOS benefitEpidermal growth factor receptor tyrosine kinaseII trialIdentification of EGFR mutation, KRAS mutation, and ALK gene rearrangement in cytological specimens of primary and metastatic lung adenocarcinoma
Cai G, Wong R, Chhieng D, Levy GH, Gettinger SN, Herbst RS, Puchalski JT, Homer RJ, Hui P. Identification of EGFR mutation, KRAS mutation, and ALK gene rearrangement in cytological specimens of primary and metastatic lung adenocarcinoma. Cancer Cytopathology 2013, 121: 500-507. PMID: 23495083, DOI: 10.1002/cncy.21288.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdultAgedAged, 80 and overAnaplastic Lymphoma KinaseBiomarkers, TumorBone NeoplasmsCytodiagnosisDNA, NeoplasmErbB ReceptorsFeasibility StudiesFemaleGene RearrangementHumansIn Situ Hybridization, FluorescenceLiver NeoplasmsLung NeoplasmsMaleMiddle AgedMutationNeoplasm Recurrence, LocalPrognosisProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)Ras ProteinsReal-Time Polymerase Chain ReactionReceptor Protein-Tyrosine KinasesSoft Tissue NeoplasmsYoung AdultConceptsALK gene rearrangementMetastatic lung adenocarcinomaEGFR mutationsKRAS mutationsMetastatic tumorsEpidermal growth factor receptorLung adenocarcinomaCytological specimensGene rearrangementsMolecular testsMolecular alterationsKirsten rat sarcoma viral oncogene homolog (KRAS) mutationsALK gene rearrangement analysisAnaplastic lymphoma kinase (ALK) gene rearrangementEGFR T790M mutationRat sarcoma viral oncogene homolog mutationsCases of lungT790M mutationImportant therapeutic implicationsFine needle aspiratesGene rearrangement analysisCell block materialGrowth factor receptorRecurrent lungRecurrent adenocarcinoma
2012
A step towards treating KRAS-mutant NSCLC
Goldberg SB, Schlessinger J, Boyer JL, Herbst RS. A step towards treating KRAS-mutant NSCLC. The Lancet Oncology 2012, 14: 3-5. PMID: 23200176, DOI: 10.1016/s1470-2045(12)70528-4.Peer-Reviewed Original ResearchCombined MEK and VEGFR Inhibition in Orthotopic Human Lung Cancer Models Results in Enhanced Inhibition of Tumor Angiogenesis, Growth, and Metastasis
Takahashi O, Komaki R, Smith PD, Jürgensmeier JM, Ryan A, Bekele BN, Wistuba II, Jacoby JJ, Korshunova MV, Biernacka A, Erez B, Hosho K, Herbst RS, O'Reilly MS. Combined MEK and VEGFR Inhibition in Orthotopic Human Lung Cancer Models Results in Enhanced Inhibition of Tumor Angiogenesis, Growth, and Metastasis. Clinical Cancer Research 2012, 18: 1641-1654. PMID: 22275507, PMCID: PMC3306446, DOI: 10.1158/1078-0432.ccr-11-2324.Peer-Reviewed Original ResearchMeSH KeywordsAngiogenesis InhibitorsAnimalsAntineoplastic Combined Chemotherapy ProtocolsBenzimidazolesCarcinoma, Non-Small-Cell LungCell Line, TumorCell ProliferationDisease ProgressionHumansLung NeoplasmsMaleMiceMice, NudeMitogen-Activated Protein KinasesMolecular Targeted TherapyNeovascularization, PathologicPaclitaxelProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)QuinazolinesRas ProteinsReceptors, Vascular Endothelial Growth FactorXenograft Model Antitumor AssaysConceptsSignal-regulated kinase kinaseTumor cell proliferationCell proliferationReceptor tyrosine kinasesKinase kinaseAvailable MEK1/2 inhibitorHuman NSCLC cellsTyrosine kinaseVEGF receptor tyrosine kinasesERK phosphorylationNCI-H441MEK1/2 inhibitorApoptotic effectsAdjacent normal tissuesKinaseNSCLC cellsMEK inhibitionAntiangiogenic effectsSignalingOrthotopic human lung cancer modelAvailable potent inhibitorLung tumor growthPotent inhibitorTumor angiogenesisSelumetinib
2010
Phase II Selection Design Trial of Concurrent Chemotherapy and Cetuximab Versus Chemotherapy Followed by Cetuximab in Advanced-Stage Non–Small-Cell Lung Cancer: Southwest Oncology Group Study S0342
Herbst RS, Kelly K, Chansky K, Mack PC, Franklin WA, Hirsch FR, Atkins JN, Dakhil SR, Albain KS, Kim ES, Redman M, Crowley JJ, Gandara DR. Phase II Selection Design Trial of Concurrent Chemotherapy and Cetuximab Versus Chemotherapy Followed by Cetuximab in Advanced-Stage Non–Small-Cell Lung Cancer: Southwest Oncology Group Study S0342. Journal Of Clinical Oncology 2010, 28: 4747-4754. PMID: 20921467, PMCID: PMC3020704, DOI: 10.1200/jco.2009.27.9356.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorCarboplatinCarcinoma, Non-Small-Cell LungCetuximabDisease-Free SurvivalDrug Administration ScheduleErbB ReceptorsErlotinib HydrochlorideFemaleHumansKaplan-Meier EstimateLung NeoplasmsMaleMiddle AgedMutationNeoplasm StagingPaclitaxelPatient SelectionProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)QuinazolinesRas ProteinsResearch DesignSouthwestern United StatesTreatment OutcomeConceptsCell lung cancerConcurrent chemotherapyLung cancerEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsProgression-free survival timeRandomized phase II trialReceptor tyrosine kinase inhibitorsMedian overall survivalPaclitaxel/carboplatinTreatment-naive patientsGrade 3 rashPhase II trialAdvanced-stage NSCLCPhase III evaluationTyrosine kinase inhibitorsEnhanced antitumor activityConcurrent regimenMaintenance cetuximabMedian followVersus ChemotherapyChemotherapy regimenII trialSequential therapyConcurrent therapy
2009
Integration of Molecular Profiling into the Lung Cancer Clinic
Pao W, Kris MG, Iafrate AJ, Ladanyi M, Jänne PA, Wistuba II, Miake-Lye R, Herbst RS, Carbone DP, Johnson BE, Lynch TJ. Integration of Molecular Profiling into the Lung Cancer Clinic. Clinical Cancer Research 2009, 15: 5317-5322. PMID: 19706816, DOI: 10.1158/1078-0432.ccr-09-0913.Peer-Reviewed Original ResearchConceptsMolecular profilingLung cancer clinicThoracic oncology centersMore effective treatmentsMedical oncologyOncology centersAppropriate trialsLung cancerOncology practiceCancer clinicEffective treatmentSide effectsMolecular aberrationsNecessary end pointEnd pointPatientsRoutine partTherapyAppropriate candidatesTrialsRare mutationsAdequate numberStandardized methodMultiple institutionsEarly stages
2008
Molecular Characteristics of Bronchioloalveolar Carcinoma and Adenocarcinoma, Bronchioloalveolar Carcinoma Subtype, Predict Response to Erlotinib
Miller VA, Riely GJ, Zakowski MF, Li AR, Patel JD, Heelan RT, Kris MG, Sandler AB, Carbone DP, Tsao A, Herbst RS, Heller G, Ladanyi M, Pao W, Johnson DH. Molecular Characteristics of Bronchioloalveolar Carcinoma and Adenocarcinoma, Bronchioloalveolar Carcinoma Subtype, Predict Response to Erlotinib. Journal Of Clinical Oncology 2008, 26: 1472-1478. PMID: 18349398, DOI: 10.1200/jco.2007.13.0062.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdenocarcinoma, Bronchiolo-AlveolarAdultAgedAged, 80 and overAntineoplastic AgentsBiomarkers, TumorDisease-Free SurvivalErbB ReceptorsErlotinib HydrochlorideFemaleHumansImmunohistochemistryLung NeoplasmsMaleMiddle AgedMutationProtein Kinase InhibitorsProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)QuinazolinesRas ProteinsSuppressor of Cytokine Signaling ProteinsTreatment OutcomeConceptsProgression-free survivalBronchioloalveolar carcinomaResponse rateEGFR mutationsEGFR immunohistochemistryKRAS mutationsEpidermal growth factor receptor (EGFR) mutationsPrimary end pointEfficacy of erlotinibPhase II trialSubset of patientsCell lung cancerBAC subtypeOverall response rateKRAS mutation statusPure bronchioloalveolar carcinomaBronchioloalveolar carcinoma (BAC) subtypeMolecular characteristicsMedian OSII trialMedian survivalOverall survivalHistologic subtypeLung cancerUnivariate analysis
2007
KRAS Mutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer
Massarelli E, Varella-Garcia M, Tang X, Xavier AC, Ozburn NC, Liu DD, Bekele BN, Herbst RS, Wistuba II. KRAS Mutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer. Clinical Cancer Research 2007, 13: 2890-2896. PMID: 17504988, DOI: 10.1158/1078-0432.ccr-06-3043.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, Non-Small-Cell LungDisease ProgressionDrug Resistance, NeoplasmErbB ReceptorsErlotinib HydrochlorideFemaleGefitinibGene DosageHumansLung NeoplasmsMaleMiddle AgedMutationPrognosisProtein Kinase InhibitorsProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)QuinazolinesRas ProteinsTreatment OutcomeConceptsEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsReceptor tyrosine kinase inhibitorsCell lung cancerKRAS mutationsTyrosine kinase inhibitorsEGFR-TKIEGFR copy numberEGFR mutationsLung cancerFavorable responseKinase inhibitorsShorter median timeArchival tissue specimensEGFR gene mutationsPanel of markersAdvanced NSCLCObjective responseProgressive diseaseSurvival benefitMedian timePoor responseSuch therapyDisease progressionPatients