Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies
Nayar U, Cohen O, Kapstad C, Cuoco MS, Waks AG, Wander SA, Painter C, Freeman S, Persky NS, Marini L, Helvie K, Oliver N, Rozenblatt-Rosen O, Ma CX, Regev A, Winer EP, Lin NU, Wagle N. Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies. Nature Genetics 2018, 51: 207-216. PMID: 30531871, DOI: 10.1038/s41588-018-0287-5.Peer-Reviewed Original ResearchConceptsHER2 mutationsEstrogen receptorBreast cancerClinical resistance mechanismsMainstay of treatmentMetastatic breast cancerReceptor-directed therapyCDK6 inhibitor palbociclibPre-existing mutationsMetastatic settingEstrogen independenceInhibitor palbociclibPrimary tumorMetastatic biopsiesInhibitor neratinibTherapyPatientsER mutationsCancerTamoxifenResistance mechanismsDistinct mechanismsMutationsConfer resistanceBiopsyAllele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations
Jeselsohn R, Bergholz JS, Pun M, Cornwell M, Liu W, Nardone A, Xiao T, Li W, Qiu X, Buchwalter G, Feiglin A, Abell-Hart K, Fei T, Rao P, Long H, Kwiatkowski N, Zhang T, Gray N, Melchers D, Houtman R, Liu XS, Cohen O, Wagle N, Winer EP, Zhao J, Brown M. Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations. Cancer Cell 2018, 33: 173-186.e5. PMID: 29438694, PMCID: PMC5813700, DOI: 10.1016/j.ccell.2018.01.004.Peer-Reviewed Original ResearchConceptsChromatin recruitmentLigand-independent functionsER mutationsPro-metastatic phenotypeGenetic screenTranscriptional networksTranscriptional programsWild-type ERTherapeutic vulnerabilitiesPotential therapeutic targetMutationsMutantsDomain mutationsLigand-binding domain mutationsActivating mutationsTherapeutic targetTherapy resistanceUnique recruitmentRecruitmentGenetic vulnerabilityCancer modelGenesBreast cancer modelERPhenotype