title: Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer.
abstract: OBJECTIVE
  Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains first-line therapy for the management of estrogen receptor (ESR1)-positive breast cancer. However, ESR1 mutations or other ligand-independent ESR1 activation mechanisms limit the duration of response. The clinical efficacy of fulvestrant, a selective estrogen receptor downregulator (SERD) that competitively inhibits agonist binding to ESR1 and triggers receptor downregulation, has confirmed that ESR1 frequently remains engaged in endocrine therapy-resistant cancers. We evaluated the activity of a new class of selective estrogen receptor modulators (SERM)/SERD hybrids (SSH) that downregulate ESR1 in relevant models of endocrine-resistant breast cancer. Building on the observation that concurrent inhibition of ESR1 and the cyclin-dependent kinases 4 and 6 (CDK4/6) significantly increased progression-free survival in advanced patients, we explored the activity of different SERD- or SSH-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant ESR1(+) breast cancer.
  
  
  METHODS
  SERDs, SSHs, and the CDK4/6 inhibitor palbociclib were evaluated as single agents or in combination in established cellular and animal models of endocrine therapy-resistant ESR1(+) breast cancer.
  
  
  RESULTS
  The combination of palbociclib with a SERD or an SSH was shown to effectively inhibit the growth of MCF7 cell or ESR1-mutant patient-derived tumor xenografts. In tamoxifen-resistant MCF7 xenografts, the palbociclib/SERD or SSH combination resulted in an increased duration of response as compared with either drug alone.
  
  
  CONCLUSIONS
  A SERD- or SSH-palbociclib combination has therapeutic potential in breast tumors resistant to endocrine therapies or those expressing ESR1 mutations. See related commentary by DeMichele and Chodosh, p. 4999.
authors.affiliation: Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham, NC 27710.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Wardell
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine Houston TX 77030.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham, NC 27710.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Alley
authors.affiliation: Pfizer Oncology Research Unit La Jolla, CA 92121.
authors.forename: Koleen
authors.initials: K
authors.lastname: Eisele
authors.affiliation: Pfizer Oncology Research Unit La Jolla, CA 92121.
authors.forename: Todd
authors.initials: T
authors.lastname: VanArsdale
authors.affiliation: Pfizer Oncology Research Unit La Jolla, CA 92121.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Dann
authors.affiliation: Pfizer Oncology Research Unit Pearl River, NY 10965.
authors.forename: Kim T
authors.initials: KT
authors.lastname: Arndt
authors.affiliation: Division of Oncology, Department of Internal Medicine Washington University in St Louis, MO 63110.
authors.forename: Tina
authors.initials: T
authors.lastname: Primeau
authors.affiliation: Division of Oncology, Department of Internal Medicine Washington University in St Louis, MO 63110.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Griffin
authors.affiliation: Division of Oncology, Department of Internal Medicine Washington University in St Louis, MO 63110.
authors.forename: Jieya
authors.initials: J
authors.lastname: Shao
authors.affiliation: Division of Oncology, Department of Internal Medicine Washington University in St Louis, MO 63110.
authors.forename: Robert
authors.initials: R
authors.lastname: Crowder
authors.affiliation: Department of Pathology Saint Louis University, MO 63104.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Lai
authors.affiliation: Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham, NC 27710.
authors.forename: John D
authors.initials: JD
authors.lastname: Norris
authors.affiliation: Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham, NC 27710.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.affiliation: Division of Oncology, Department of Internal Medicine Washington University in St Louis, MO 63110.|Siteman Cancer Center Breast Cancer Program Washington University in St. Louis, MO 63110.
authors.forename: Shunqiang
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000235:genetics*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009154:Mutation; D010879:Piperazines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage*; D013629:Tamoxifen / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D010879:Piperazines; D011725:Pyridines; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib