title: AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules.
abstract: mTOR is an atypical serine threonine kinase involved in regulating major cellular functions, such as nutrients sensing, growth, and proliferation. mTOR is part of the multiprotein complexes mTORC1 and mTORC2, which have been shown to play critical yet functionally distinct roles in the regulation of cellular processes. Current clinical mTOR inhibitors only inhibit the mTORC1 complex and are derivatives of the macrolide rapamycin (rapalogs). Encouraging effects have been observed with rapalogs in estrogen receptor-positive (ER(+)) breast cancer patients in combination with endocrine therapy, such as aromatase inhibitors. AZD2014 is a small-molecule ATP competitive inhibitor of mTOR that inhibits both mTORC1 and mTORC2 complexes and has a greater inhibitory function against mTORC1 than the clinically approved rapalogs. Here, we demonstrate that AZD2014 has broad antiproliferative effects across multiple cell lines, including ER(+) breast models with acquired resistance to hormonal therapy and cell lines with acquired resistance to rapalogs. In vivo, AZD2014 induces dose-dependent tumor growth inhibition in several xenograft and primary explant models. The antitumor activity of AZD2014 is associated with modulation of both mTORC1 and mTORC2 substrates, consistent with its mechanism of action. In combination with fulvestrant, AZD2014 induces tumor regressions when dosed continuously or using intermittent dosing schedules. The ability to dose AZD2014 intermittently, together with its ability to block signaling from both mTORC1 and mTORC2 complexes, makes this compound an ideal candidate for combining with endocrine therapies in the clinic. AZD2014 is currently in phase II clinical trials.
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts.
authors.forename: Sylvie M
authors.initials: SM
authors.lastname: Guichard
authors.affiliation: AstraZeneca Oncology, Macclesfield, Cheshire, United Kingdom.
authors.forename: Jon
authors.initials: J
authors.lastname: Curwen
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts.
authors.forename: Teeru
authors.initials: T
authors.lastname: Bihani
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts.
authors.forename: Celina M
authors.initials: CM
authors.lastname: D'Cruz
authors.affiliation: AstraZeneca Oncology, CRUK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: James W T
authors.initials: JW
authors.lastname: Yates
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Grondine
authors.affiliation: Roche, Basel, Switzerland.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Howard
authors.affiliation: AstraZeneca Oncology, Macclesfield, Cheshire, United Kingdom.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.affiliation: AstraZeneca Oncology, Macclesfield, Cheshire, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Bigley
authors.affiliation: AstraZeneca Oncology, Macclesfield, Cheshire, United Kingdom.
authors.forename: Teresa
authors.initials: T
authors.lastname: Klinowska
authors.affiliation: AstraZeneca Oncology, Cambridge, United Kingdom.
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Pike
authors.affiliation: AstraZeneca Oncology, Cambridge, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Pass
authors.affiliation: AstraZeneca Oncology, Macclesfield, Cheshire, United Kingdom.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Chresta
authors.affiliation: AstraZeneca Oncology, Macclesfield, Cheshire, United Kingdom.
authors.forename: Urszula M
authors.initials: UM
authors.lastname: Polanska
authors.affiliation: AstraZeneca Oncology, Macclesfield, Cheshire, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: McEwen
authors.affiliation: AstraZeneca Oncology, CRUK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: Oona
authors.initials: O
authors.lastname: Delpuech
authors.affiliation: AstraZeneca Oncology, Macclesfield, Cheshire, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
authors.affiliation: AstraZeneca Oncology, CRUK Cambridge Institute, Cambridge, United Kingdom. sabina.cosulich@astrazeneca.com.
authors.forename: Sabina C
authors.initials: SC
authors.lastname: Cosulich
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001549:Benzamides; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004334:Drug Administration Schedule; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009025:Morpholines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D001549:Benzamides; D009025:Morpholines; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011960:Receptors, Estrogen; C585537:vistusertib; D000077267:Fulvestrant; D004958:Estradiol; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases