title: Effective combination therapies in preclinical endocrine resistant breast cancer models harboring ER mutations.
abstract: Although endocrine therapy is successfully used to treat patients with estrogen receptor (ER) positive breast cancer, a substantial proportion of this population will relapse. Several mechanisms of acquired resistance have been described including activation of the mTOR pathway, increased activity of CDK4 and activating mutations in ER. Using a patient derived xenograft model harboring a common activating ER ligand binding domain mutation (D538G), we evaluated several combinatorial strategies using the selective estrogen receptor degrader (SERD) fulvestrant in combination with chromatin modifying agents, and CDK4/6 and mTOR inhibitors. In this model, fulvestrant binds WT and MT ER, reduces ER protein levels, and downregulated ER target gene expression. Addition of JQ1 or vorinostat to fulvestrant resulted in tumor regression (41% and 22% regression, respectively) though no efficacy was seen when either agent was given alone. Interestingly, although the CDK4/6 inhibitor palbociclib and mTOR inhibitor everolimus were efficacious as monotherapies, long-term delayed tumor growth was only observed when co-administered with fulvestrant. This observation was consistent with a greater inhibition of compensatory signaling when palbociclib and everolimus were co-dosed with fulvestrant. The addition of fulvestrant to JQ1, vorinostat, everolimus and palbociclib also significantly reduced lung metastatic burden as compared to monotherapy. The combination potential of fulvestrant with palbociclib or everolimus were confirmed in an MCF7 CRISPR model harboring the Y537S ER activating mutation. Taken together, these data suggest that fulvestrant may have an important role in the treatment of ER positive breast cancer with acquired ER mutations.
authors.affiliation: Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Brendon
authors.initials: B
authors.lastname: Ladd
authors.affiliation: Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Mazzola
authors.affiliation: Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Teeru
authors.initials: T
authors.lastname: Bihani
authors.affiliation: Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Lai
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bradford
authors.affiliation: Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Collins
authors.affiliation: Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Barry
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Anne U
authors.initials: AU
authors.lastname: Goeppert
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Weir
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hearne
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Renshaw
authors.affiliation: Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Morvarid
authors.initials: M
authors.lastname: Mohseni
authors.affiliation: Oncology, Medimmune, Gaithersburg, MD, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Hurt
authors.affiliation: Oncology, Medimmune, Gaithersburg, MD, USA.
authors.forename: Sanjoo
authors.initials: S
authors.lastname: Jalla
authors.affiliation: Oncology, Medimmune, Gaithersburg, MD, USA.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Bao
authors.affiliation: Oncology, Medimmune, Gaithersburg, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hollingsworth
authors.affiliation: Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Reimer
authors.affiliation: Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Zinda
authors.affiliation: Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fawell
authors.affiliation: Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Celina M
authors.initials: CM
authors.lastname: D'Cruz
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068338:Everolimus / Q000008:administration & dosage; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009154:Mutation; D010879:Piperazines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011960:Receptors, Estrogen / Q000032:analysis / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010879:Piperazines; D011725:Pyridines; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib
keywords: ER mutations; advanced metastatic breast cancer; combination therapy; endocrine resistance