title: The PI3K/mTOR dual inhibitor P7170 demonstrates potent activity against endocrine-sensitive and endocrine-resistant ER+ breast cancer.
abstract: Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway has been implicated in anti-estrogen resistance in breast cancer. We tested the therapeutic potential of the novel PI3K/mTOR dual inhibitor P7170 in a panel of anti-estrogen-sensitive and anti-estrogen-resistant models of ER+ breast cancer. Estrogen receptor-positive (ER+) breast cancer cells were treated ±P7170. Fresh cores from primary ER+/HER2- tumors from two patients were treated ±P7170 ex vivo. Mice bearing breast cancer xenografts were randomized to treatment with vehicle, fulvestrant, P7170, or combinations, and tumor volumes were measured. Tissues and cells were analyzed for markers of pathway activity, cell viability, and apoptosis. In cell lines, P7170 exhibited IC50 values in the range of 0.9-7 nM and induced apoptosis. P7170 potently inhibited mTOR activity (≤ 25 nM) and inhibited PI3K at higher concentrations (≥ 200 nM). P7170 completely inhibited MCF-7 tumor growth, significantly inhibited growth of fulvestrant-resistant T47D tumors, and suppressed tumor cell proliferation but did not induce apoptosis. While P7170 inhibits PI3K and mTOR in ER+/HER2- human breast cancer cells and tumors ex vivo, in vivo data indicate that the primary mechanism of P7170 anti-tumor action is inhibition of mTOR and cell proliferation. P7170 is a novel agent worthy of further investigation for the treatment of ER+ breast cancer.
authors.affiliation: Department of Pharmacology & Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, One Medical Center Dr., Lebanon, NH, 03756, USA, jennifer.r.bean@dartmouth.edu.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Bean
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Hosford
authors.forename: Lynn K
authors.initials: LK
authors.lastname: Symonds
authors.forename: Philip
authors.initials: P
authors.lastname: Owens
authors.forename: Lloye M
authors.initials: LM
authors.lastname: Dillon
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Kevin
authors.initials: K
authors.lastname: Shee
authors.forename: Gary N
authors.initials: GN
authors.lastname: Schwartz
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Marotti
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Muller
authors.forename: Kari M
authors.initials: KM
authors.lastname: Rosenkranz
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Barth
authors.forename: Vivian S
authors.initials: VS
authors.lastname: Chen
authors.forename: Veena R
authors.initials: VR
authors.lastname: Agarwal
authors.forename: Todd W
authors.initials: TW
authors.lastname: Miller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004701:Endocrine Gland Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D061986:MCF-7 Cells; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage*; D011960:Receptors, Estrogen / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004958:Estradiol; D000077267:Fulvestrant; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D011960:Receptors, Estrogen; D058570:TOR Serine-Threonine Kinases; C000601501:P7170 compound; C546842:MTOR protein, human