title: ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer.
abstract: Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the expression of ERRα is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring mitochondrial energy metabolism through increased glutamine metabolism, as well as ROS detoxification required for cell survival under therapeutic stress conditions. An ERRα inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mammary tumour mouse model. This work reveals a molecular mechanism by which ERRα-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERRα inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada H3A 1A3.|Department of Biochemistry, McGill University, Montréal, Québec, Canada H3G 1Y6.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Deblois
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada H3A 1A3.
authors.forename: Harvey W
authors.initials: HW
authors.lastname: Smith
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada H3A 1A3.
authors.forename: Ingrid S
authors.initials: IS
authors.lastname: Tam
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada H3A 1A3.
authors.forename: Simon-Pierre
authors.initials: SP
authors.lastname: Gravel
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Québec, Canada H3G 1Y6.
authors.forename: Maxime
authors.identifier: 0000-0002-3733-5723
authors.initials: M
authors.lastname: Caron
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada H3A 1A3.|Department of Medicine, McGill University, Montréal, Québec, Canada H3A 1A3.
authors.forename: Paul
authors.initials: P
authors.lastname: Savage
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada H3A 1A3.|Department of Medicine, McGill University, Montréal, Québec, Canada H3A 1A3.
authors.forename: David P
authors.initials: DP
authors.lastname: Labbé
authors.affiliation: Service d'anatomopathologie, Hôpital du Sacré-Cœur de Montréal, 5400 Boulevard Gouin Ouest, Montréal, Québec, Canada H4J 1C5.
authors.forename: Louis R
authors.initials: LR
authors.lastname: Bégin
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada H3A 1A3.|Department of Biochemistry, McGill University, Montréal, Québec, Canada H3G 1Y6.|Department of Medicine, McGill University, Montréal, Québec, Canada H3A 1A3.|Department of Oncology, McGill University, Montréal, Québec, Canada H2W 1S6.
authors.forename: Michel L
authors.identifier: 0000-0002-0281-541X
authors.initials: ML
authors.lastname: Tremblay
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada H3A 1A3.|Department of Biochemistry, McGill University, Montréal, Québec, Canada H3G 1Y6.|Department of Medicine, McGill University, Montréal, Québec, Canada H3A 1A3.|Department of Oncology, McGill University, Montréal, Québec, Canada H2W 1S6.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Québec, Canada H3G 1Y6.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada H3A 1A3.|Department of Biochemistry, McGill University, Montréal, Québec, Canada H3G 1Y6.
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada H3A 1A3.|Department of Biochemistry, McGill University, Montréal, Québec, Canada H3G 1Y6.|Department of Medicine, McGill University, Montréal, Québec, Canada H3A 1A3.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada H3A 1A3.|Department of Biochemistry, McGill University, Montréal, Québec, Canada H3G 1Y6.|Department of Medicine, McGill University, Montréal, Québec, Canada H3A 1A3.|Department of Oncology, McGill University, Montréal, Québec, Canada H2W 1S6.
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D000077341:Lapatinib; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics*; D012192:Retroviridae Infections; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014412:Tumor Virus Infections; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D058570:TOR Serine-Threonine Kinases; D000097983:ERRalpha Estrogen-Related Receptor; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse