2021
Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies
Lukow DA, Sausville EL, Suri P, Chunduri NK, Wieland A, Leu J, Smith JC, Girish V, Kumar AA, Kendall J, Wang Z, Storchova Z, Sheltzer JM. Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies. Developmental Cell 2021, 56: 2427-2439.e4. PMID: 34352222, PMCID: PMC8933054, DOI: 10.1016/j.devcel.2021.07.009.Peer-Reviewed Original ResearchMeSH KeywordsAneuploidyCell Line, TumorChromosomal InstabilityDrug ResistanceEnvironmentHumansNeoplasmsTreatment OutcomeConceptsChromosomal instabilityAnti-cancer therapyCancer cell fitnessAcquisition of aneuploidyChromosome loss eventsSingle-cell sequencingEvolution of resistanceDifferent culture environmentsCellular fitnessPhenotypic plasticityCIN correlatesHuman tumorsCell fitnessHuman cellsStressful environmentsResistant populationsAcquisition of resistanceRecurrent aneuploidyCancer cellsPaclitaxel-resistant cellsCulture environmentAneuploidyPaclitaxel sensitivityFitnessCellsAneuploidy as a promoter and suppressor of malignant growth
Vasudevan A, Schukken KM, Sausville EL, Girish V, Adebambo OA, Sheltzer JM. Aneuploidy as a promoter and suppressor of malignant growth. Nature Reviews Cancer 2021, 21: 89-103. PMID: 33432169, DOI: 10.1038/s41568-020-00321-1.Peer-Reviewed Original Research
2020
Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division
Replogle JM, Zhou W, Amaro AE, McFarland JM, Villalobos-Ortiz M, Ryan J, Letai A, Yilmaz O, Sheltzer J, Lippard SJ, Ben-David U, Amon A. Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 30566-30576. PMID: 33203674, PMCID: PMC7720170, DOI: 10.1073/pnas.2009506117.Peer-Reviewed Original ResearchConceptsCell cycle delayG1 cell cycle delayChromosome gainsSingle chromosome gainsCycle delayWhole chromosome gainsCancer Cell Line Encyclopedia (CCLE) datasetsDrug resistanceCell divisionCellular stressEuploid cellsPoor disease outcomeG1 delayPoor patient prognosisS phaseSelective benefitsSlow proliferationChemotherapeutic cisplatinChemotherapeutic resistanceCancer cellsSlowed proliferationChemotherapy treatmentPatient prognosisDisease outcomeAneuploidy
2019
Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials
Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, Sausville EL, Lukow DA, Liu L, Chait AR, Galluzzo ZC, Tucker C, Sheltzer JM. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science Translational Medicine 2019, 11 PMID: 31511426, PMCID: PMC7717492, DOI: 10.1126/scitranslmed.aaw8412.Peer-Reviewed Original ResearchConceptsClinical trialsCancer drugsDose-limiting toxicityLack of efficacyDrug Administration approvalNumber of therapiesCancer cell proliferationMultiple cancer typesMechanism of actionClinical benefitAdministration approvalCommon causeTrial failuresSmall molecule inhibitorsClinical testingCDK11 expressionHuman patientsPreclinical settingCancer typesU.S. FoodTarget toxicityNew drugsDrugsCell proliferationDrug-indication pairs
2018
MELK expression correlates with tumor mitotic activity but is not required for cancer growth
Giuliano C, Lin A, Smith J, Palladino A, Sheltzer J. MELK expression correlates with tumor mitotic activity but is not required for cancer growth. ELife 2018, 7: e32838. PMID: 29417930, PMCID: PMC5805410, DOI: 10.7554/elife.32838.Peer-Reviewed Original ResearchConceptsMaternal embryonic leucine zipper kinaseTumor mitotic activityCancer typesMitotic activityPoor clinical prognosisBreast cancer cell linesPromising therapeutic targetTriple-negative breast cancer cell linesEmbryonic leucine zipper kinaseMultiple cancer typesLeucine zipper kinaseCancer cell linesCytotoxic chemotherapyAggressive diseaseCancer patientsClinical prognosisMELK expressionTherapeutic targetChemotherapy resistanceCancer growthTumor growthAcute inhibitionMELK inhibitorExpression correlatesCancer-related processes
2017
CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on-going clinical trials
Lin A, Giuliano C, Sayles N, Sheltzer J. CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on-going clinical trials. ELife 2017, 6: e24179. PMID: 28337968, PMCID: PMC5365317, DOI: 10.7554/elife.24179.Peer-Reviewed Original ResearchConceptsMaternal embryonic leucine zipper kinaseClinical trialsCancer cell linesBasal breast cancer cell linesCancer typesCell linesNovel chemotherapy agentsTriple-negative subtypeCurrent clinical trialsBreast cancer cell linesEmbryonic leucine zipper kinaseLeucine zipper kinaseMELK knockdownBreast cancerChemotherapy agentsPreclinical resultsSmall molecule inhibitorsAnchorage-independent growthMELK inhibitorTarget mechanismsPreclinical target validationTrialsDoubling timeTarget validationInhibitors