1. AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules.
- Author
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Guichard SM, Curwen J, Bihani T, D'Cruz CM, Yates JW, Grondine M, Howard Z, Davies BR, Bigley G, Klinowska T, Pike KG, Pass M, Chresta CM, Polanska UM, McEwen R, Delpuech O, Green S, and Cosulich SC
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Benzamides, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Cell Proliferation drug effects, Drug Administration Schedule, Estradiol administration & dosage, Estradiol analogs & derivatives, Estradiol pharmacology, Female, Fulvestrant, HEK293 Cells, Humans, Immunoblotting, MCF-7 Cells, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Morpholines administration & dosage, Morpholines chemistry, Multiprotein Complexes metabolism, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors pharmacology, Pyrimidines, Receptors, Estrogen metabolism, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism, Tumor Burden drug effects, Xenograft Model Antitumor Assays methods, Breast Neoplasms drug therapy, Morpholines pharmacology, Multiprotein Complexes antagonists & inhibitors, TOR Serine-Threonine Kinases antagonists & inhibitors
- 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., (©2015 American Association for Cancer Research.)
- Published
- 2015
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