Combined Inhibition of mTOR and CDK4/6 Is Required for Optimal Blockade of E2F Function and Long-term Growth Inhibition in Estrogen Receptor-positive Breast Cancer.


Type
Article
Change log
Authors
Michaloglou, Chrysiis 
Crafter, Claire 
Siersbaek, Rasmus 
Delpuech, Oona 
Curwen, Jon O 
Abstract

The cyclin dependent kinase (CDK)-retinoblastoma (RB)-E2F pathway plays a critical role in the control of cell cycle in estrogen receptor-positive (ER+) breast cancer. Small-molecule inhibitors of CDK4/6 have shown promise in this tumor type in combination with hormonal therapies, reflecting the particular dependence of this subtype of cancer on cyclin D1 and E2F transcription factors. mTOR inhibitors have also shown potential in clinical trials in this disease setting. Recent data have suggested cooperation between the PI3K/mTOR pathway and CDK4/6 inhibition in preventing early adaptation and eliciting growth arrest, but the mechanisms of the interplay between these pathways have not been fully elucidated. Here we show that profound and durable inhibition of ER+ breast cancer growth is likely to require multiple hits on E2F-mediated transcription. We demonstrate that inhibition of mTORC1/2 does not affect ER function directly, but does cause a decrease in cyclin D1 protein, RB phosphorylation, and E2F-mediated transcription. Combination of an mTORC1/2 inhibitor with a CDK4/6 inhibitor results in more profound effects on E2F-dependent transcription, which translates into more durable growth arrest and a delay in the onset of resistance. Combined inhibition of mTORC1/2, CDK4/6, and ER delivers even more profound and durable regressions in breast cancer cell lines and xenografts. Furthermore, we show that CDK4/6 inhibitor-resistant cell lines reactivate the CDK-RB-E2F pathway, but remain sensitive to mTORC1/2 inhibition, suggesting that mTORC1/2 inhibitors may represent an option for patients that have relapsed on CDK4/6 therapy. Mol Cancer Ther; 17(5); 908-20. ©2018 AACR.

Description
Keywords
Animals, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, E2F Transcription Factors, Female, Humans, MCF-7 Cells, Mice, SCID, Morpholines, Piperazines, Pyridines, Pyrimidines, Receptors, Estrogen, TOR Serine-Threonine Kinases, Xenograft Model Antitumor Assays
Journal Title
Mol Cancer Ther
Conference Name
Journal ISSN
1535-7163
1538-8514
Volume Title
17
Publisher
American Association for Cancer Research
Sponsorship
Cancer Research UK (C14303/A17197)
CRUK Cambridge Institute, Cambridge, UK (Jason Carroll, Igor Chernukhin, Rasmus Siersbæk3) Novo Nordisk Fonden (NNF 14136) (Rasmus Siersbæk)