| First Author | Deblois G | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 12156 | PubMed ID | 27402251 |
| Mgi Jnum | J:240837 | Mgi Id | MGI:5896492 |
| Doi | 10.1038/ncomms12156 | Citation | Deblois G, et al. (2016) ERRalpha mediates metabolic adaptations driving lapatinib resistance in breast cancer. Nat Commun 7:12156 |
| abstractText | 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 ERRalpha, a master regulator of cellular metabolism, and that the expression of ERRalpha is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRalpha 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 ERRalpha 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 ERRalpha-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERRalpha inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer. |
