ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer

• Published in: Nature communications 2016-07, Vol.7 (1), p.12156-12156, Article 12156
• Main Authors: Deblois, Geneviève, Smith, Harvey W., Tam, Ingrid S., Gravel, Simon-Pierre, Caron, Maxime, Savage, Paul, Labbé, David P., Bégin, Louis R., Tremblay, Michel L., Park, Morag, Bourque, Guillaume, St-Pierre, Julie, Muller, William J., Giguère, Vincent
• Format: Article
• Language: English
• Subjects: 38; 38/109; 38/15; 38/39; 38/61; 38/77; 631/80/86; 692/699/67/1059/2326; 692/699/67/1347; 96; 96/95; Animals; Antineoplastic Agents - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cell Survival; Drug Resistance, Neoplasm - genetics; ERRalpha Estrogen-Related Receptor; Humanities and Social Sciences; Humans; Lapatinib; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Mammary Tumor Virus, Mouse; MCF-7 Cells; Mice; multidisciplinary; Quinazolines - therapeutic use; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - genetics; Retroviridae Infections; Science; Science (multidisciplinary); Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Tumor Virus Infections
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12156

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. Despite initial benefits in treating HER2-positive breast cancer patients with lapatinib, resistance is prevalent. Here the authors show that lapatinib resistance can be ascribed to mTOR-mediated re-activation of ERRα and to the consequent induction of a metabolic adaptation.