ERR alpha mediates metabolic adaptations driving lapatinib resistance in breast cancer

作者：Deblois Genevieve; Smith Harvey W; Tam Ingrid S; Gravel Simon Pierre; Caron Maxime; Savage Paul; Labbe David P; Begin Louis R; Tremblay Michel L; Park Morag; Bourque Guillaume; St Pierre Julie; Muller William J; Giguere Vincent^*

来源：Nature Communications, 2016, 7(1): 12156.

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 ERR alpha, a master regulator of cellular metabolism, and that the expression of ERR alpha is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERR alpha 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 ERR alpha 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 ERR alpha-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERR alpha inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer.

• 出版日期2016-7