ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer

Geneviève Deblois, Harvey W. Smith, Ingrid S. Tam, Simon-Pierre Gravel, Maxime Caron, Paul Savage, David P. Labbé, Louis R. Bégin, Michel L. Tremblay, Morag Park, Guillaume Bourque, Julie St-Pierre, William J. Muller and Vincent Giguère ()
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Geneviève Deblois: Goodman Cancer Research Centre, McGill University
Harvey W. Smith: Goodman Cancer Research Centre, McGill University
Ingrid S. Tam: Goodman Cancer Research Centre, McGill University
Simon-Pierre Gravel: Goodman Cancer Research Centre, McGill University
Maxime Caron: McGill University
Paul Savage: Goodman Cancer Research Centre, McGill University
David P. Labbé: Goodman Cancer Research Centre, McGill University
Louis R. Bégin: Service d’anatomopathologie, Hôpital du Sacré-Cœur de Montréal
Michel L. Tremblay: Goodman Cancer Research Centre, McGill University
Morag Park: Goodman Cancer Research Centre, McGill University
Guillaume Bourque: McGill University
Julie St-Pierre: Goodman Cancer Research Centre, McGill University
William J. Muller: Goodman Cancer Research Centre, McGill University
Vincent Giguère: Goodman Cancer Research Centre, McGill University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12156

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