ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer

被引：89

作者：

Deblois, Genevieve ^{[1
,2
]}

Smith, Harvey W. ^{[1
]}

Tam, Ingrid S. ^{[1
]}

Gravel, Simon-Pierre ^{[1
]}

Caron, Maxime ^{[3
]}

Savage, Paul ^{[1
,4
]}

Labbe, David P. ^{[1
,4
]}

Begin, Louis R. ^{[5
]}

Tremblay, Michel L. ^{[1
,2
,4
,6
]}

Park, Morag ^{[1
,2
,4
,6
]}

Bourque, Guillaume ^{[3
]}

St-Pierre, Julie ^{[1
,2
]}

Muller, William J. ^{[1
,2
,4
]}

Giguere, Vincent ^{[1
,2
,4
,6
]}

机构：

[1] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada

[2] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada

[3] McGill Univ, Dept Human Genet, Montreal, PQ H3G 1Y6, Canada

[4] McGill Univ, Dept Med, Montreal, PQ H3A 1A3, Canada

[5] Hop Sacre Coeur, Serv Anatomopathol, 5400 Blvd Gouin Ouest, Montreal, PQ H4J 1C5, Canada

[6] McGill Univ, Dept Oncol, Montreal, PQ H2W 1S6, Canada

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

ESTROGEN-RELATED RECEPTOR; KINASE INHIBITORS; TRANSCRIPTIONAL CONTROL; MAMMARY TUMORIGENESIS; ACQUIRED-RESISTANCE; MOUSE MODEL; CELLS; SENSITIVITY; THERAPY; ACTIVATION;

D O I：

10.1038/ncomms12156

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：14

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