title: Molecular characterization of anastrozole resistance in breast cancer: pivotal role of the Akt/mTOR pathway in the emergence of de novo or acquired resistance and importance of combining the allosteric Akt inhibitor MK-2206 with an aromatase inhibitor.
abstract: Acquisition of resistance to aromatase inhibitors (AIs) remains a major drawback in the treatment of estrogen receptor alpha (ERα)-positive breast cancers. The Res-Ana cells, a new model of acquired resistance to anastrozole, were established by long-term exposure of aromatase-overexpressing MCF-7 cells to this drug. These resistant cells developed ER-independent mechanisms of resistance and decreased sensitivity to the AI letrozole or to ERα antagonists. They also displayed a constitutive activation of the PI3K/Akt/mTOR pathway and a deregulated expression of several ErbB receptors. An observed increase in the phospho-Akt/Akt ratio between primary and matched recurrent breast tumors of patients who relapsed under anastrozole adjuvant therapy also argued for a pivotal role of the Akt pathway in acquired resistance to anastrozole. Ectopic overexpression of constitutively active Akt1 in control cells was sufficient to induce de novo resistance to anastrozole. Strikingly, combining anastrozole with the highly selective and allosteric Akt inhibitor MK-2206 or with the mTOR inhibitor rapamycin increased sensitivity to this AI in the control cells and was sufficient to overcome resistance and restore sensitivity to endocrine therapy in the resistant cells. Our findings lead to us proposing a model of anastrozole-acquired resistance based on the selection of cancer-initiating-like cells possessing self-renewing properties, intrinsic resistance to anastrozole and sensitivity to MK-2206. Altogether, our work demonstrated that the Akt/mTOR pathway plays a key role in resistance to anastrozole and that combining anastrozole with Akt/mTOR pathway inhibitors represents a promising strategy in the clinical management of hormone-dependent breast cancer patients.
authors.affiliation: ISPB, Faculté de Pharmacie, Université Lyon 1, Lyon, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Vilquin
authors.forename: Marie
authors.initials: M
authors.lastname: Villedieu
authors.forename: Evelyne
authors.initials: E
authors.lastname: Grisard
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ben Larbi
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Ghayad
authors.forename: Pierre-Etienne
authors.initials: PE
authors.lastname: Heudel
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.forename: Laura
authors.initials: L
authors.lastname: Corbo
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Julie A
authors.initials: JA
authors.lastname: Vendrell
authors.forename: Pascale A
authors.initials: PA
authors.lastname: Cohen
mesh_terms: D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000096:biosynthesis; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D020893:Receptor, ErbB-3 / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D066246:ErbB Receptors; D047628:Estrogen Receptor alpha; D006575:Heterocyclic Compounds, 3-Ring; D009570:Nitriles; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014230:Triazoles; C548887:MK 2206; C546842:MTOR protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: Akt/mTOR pathway; anastrozole resistance; breast cancer; endocrine therapy; signal transduction inhibitors